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Szwarc-Hofbauer D, Simböck E, Hromada C, Stoiber M, Tomasch J, Weitzer G, Teuschl-Woller A. Purinergic receptors play a key role in shock wave-induced proliferation. Sci Rep 2025; 15:19138. [PMID: 40450090 DOI: 10.1038/s41598-025-02955-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2025] [Accepted: 05/16/2025] [Indexed: 06/03/2025] Open
Abstract
Shock wave treatment (SWT) is a non-invasive therapy applied in musculoskeletal and urological disorders, as well as in chronic wound regeneration. As the use of medical SWT broadens, it is important to better understand the molecular mechanisms underlying its success. Here, we identified P2X4 and P2Y2 purinergic receptors to be primarily expressed in C3H/10T1/2 mouse mesenchymal stromal cells and investigated their role in the initiation of the signaling events following SWT using single- and double-receptor knock-out (KO) cell lines. We show that SWT induced the expression of c-Jun and c-Fos within 30 min after stimulation and that the SWT-induced Erk1/2 pathway activation and immediate early gene expression were decreased in P2Y2-, P2X4- and P2Y2/P2X4-deficient cells. Importantly, SWT did not promote proliferation in P2Y2/P2X4-deficient cells, while loss of either one of the receptors significantly reduced the proliferative effect, indicating a cumulative effect of their loss. Finally, our data suggests a more prominent role of the P2Y2 receptor in SWT-induced cellular effects, since primarily its loss contributed to the observed changes. With these findings, we further the understanding of the molecular mechanisms of SWT and propose that the varying expression of purinergic receptors in tissues should be considered when establishing treatment protocols.
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Affiliation(s)
- Dorota Szwarc-Hofbauer
- Department Life Science Engineering, University of Applied Sciences Technikum Wien, Vienna, Austria.
- The Austrian Cluster for Tissue Regeneration, Vienna, Austria.
| | - Elisabeth Simböck
- Department Life Science Engineering, University of Applied Sciences Technikum Wien, Vienna, Austria
- The Austrian Cluster for Tissue Regeneration, Vienna, Austria
| | - Carina Hromada
- Department Life Science Engineering, University of Applied Sciences Technikum Wien, Vienna, Austria
- The Austrian Cluster for Tissue Regeneration, Vienna, Austria
| | - Michaela Stoiber
- Department Life Science Engineering, University of Applied Sciences Technikum Wien, Vienna, Austria
- The Austrian Cluster for Tissue Regeneration, Vienna, Austria
- Department of Obstetrics and Gynaecology, Medical University of Graz, Graz, Austria
| | - Janine Tomasch
- Department Life Science Engineering, University of Applied Sciences Technikum Wien, Vienna, Austria
- The Austrian Cluster for Tissue Regeneration, Vienna, Austria
| | - Georg Weitzer
- Max Perutz Labs, Vienna Biocenter Campus (VBC), Vienna, Austria
- Center for Medical Biochemistry, Department of Molecular Biology, Medical University of Vienna, Vienna, Austria
| | - Andreas Teuschl-Woller
- Department Life Science Engineering, University of Applied Sciences Technikum Wien, Vienna, Austria
- The Austrian Cluster for Tissue Regeneration, Vienna, Austria
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Hoseini SM, Montazeri F. Cell origin and microenvironment: The players of differentiation capacity in human mesenchymal stem cells. Tissue Cell 2025; 93:102709. [PMID: 39765135 DOI: 10.1016/j.tice.2024.102709] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2024] [Revised: 12/12/2024] [Accepted: 12/26/2024] [Indexed: 03/05/2025]
Abstract
Mesenchymal stem cells (MSCs) have several important properties that make them desirable for regenerative medicine. These properties include immunomodulatory ability, growth factor production, and differentiation into various cell types. Despite extensive research and promising results in clinical trials, our understanding of MSC biology, their mechanism of action, and their targeted and routine use in clinics is limited. Differentiation of human MSCs (hMSCs) is a complex process influenced by various elements such as growth factors, pharmaceutical compounds, microRNAs, 3D scaffolds, and mechanical and electrical stimulation. Research has shown that different culture conditions can affect the differentiation potential of hMSCs obtained from multiple fetal and adult sources. Additionally, it seems that what affects the differentiation capacities of these cells is their secretory characteristics, which are influenced by the origin of the cells and the local microenvironment where the cells are located. The review can provide insights into the microenvironment-based mechanisms involved in MSC differentiation, which can be valuable for future therapeutic applications.
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Affiliation(s)
- Seyed Mehdi Hoseini
- Biotechnology Research Center, Yazd Reproductive Sciences Institute, Shahid Sadoughi University of Medical Sciences and Health Services, Yazd, Iran; Hematology and Oncology Research Center, Non-communicable Diseases Research Institute, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Fateme Montazeri
- Abortion Research Center, Yazd Reproductive Sciences Institute, Shahid Sadoughi University of Medical Sciences and Health Services, Yazd, Iran.
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Yang R, Ren L, Wang H, Guo L, Liu L, Chen M, Tian X. Extracorporeal shockwave therapy for the treatment of deep dermal burns of the hand: A preliminary study. J Plast Reconstr Aesthet Surg 2025; 102:185-194. [PMID: 39938458 DOI: 10.1016/j.bjps.2025.01.050] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2024] [Revised: 12/17/2024] [Accepted: 01/24/2025] [Indexed: 02/14/2025]
Abstract
Extracorporeal shockwave therapy is used to treat chronic wounds; however, the effect on acute burn wounds of the hand has not been elucidated. We aimed to determine the healing effect of extracorporeal shockwave therapy on the wounds of patients with deep dermal hand burns, and preliminarily explore the mechanism thereof. We recruited 40 patients with deep dermal hand burns who were randomly divided into a routine dressing treatment group (n = 20) and an extracorporeal shockwave therapy group (n = 20). The wounds of the extracorporeal shockwave group were treated on days 3, 5, and 7 after injury. Percentage of wound healing, blood perfusion, infection, pain scores, and Vancouver Scar Scale of scars from 6 months after patient discharge were recorded and compared between the groups. Our method enabled us to find that the percentage of wound healing in the extracorporeal shockwave group was significantly better than that in the routine dressing treatment group. The immediate blood perfusion of wounds in the extracorporeal shockwave group after extracorporeal shockwave therapy increased significantly, and with the increase of time and treatment frequency, the wounds in the extracorporeal shockwave group reached peak blood perfusion earlier than that in the routine dressing treatment group. In conclusion, extracorporeal shockwave therapy can effectively shorten the healing time of deep dermal burns of the hand. The mechanism of action may be related to the immediate and long-term effects of increasing blood perfusion in burn wounds, while effectively reducing wound pain and controlling the spread of inflammation in the acute phase.
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Affiliation(s)
- Ruqian Yang
- Women's Health Guidance Center, Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Ling Ren
- Women's Health Guidance Center, Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Huarong Wang
- Women's Health Guidance Center, Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Ling Guo
- Women's Health Guidance Center, Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Lan Liu
- Department of Plastic and Burn Surgery, National Key Clinical Construction Specialty, Wound Repair and Regeneration Laboratory, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Meng Chen
- Women's Health Guidance Center, Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China.
| | - Xinli Tian
- Department of Plastic and Burn Surgery, National Key Clinical Construction Specialty, Wound Repair and Regeneration Laboratory, The Affiliated Hospital of Southwest Medical University, Luzhou, China.
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Beeraka NM, Basappa B, Nikolenko VN, Mahesh PA. Role of Neurotransmitters in Steady State Hematopoiesis, Aging, and Leukemia. Stem Cell Rev Rep 2025; 21:2-27. [PMID: 38976142 DOI: 10.1007/s12015-024-10761-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/02/2024] [Indexed: 07/09/2024]
Abstract
Haematopoiesis within the bone marrow (BM) represents a complex and dynamic process intricately regulated by neural signaling pathways. This delicate orchestration is susceptible to disruption by factors such as aging, diabetes, and obesity, which can impair the BM niche and consequently affect haematopoiesis. Genetic mutations in Tet2, Dnmt3a, Asxl1, and Jak2 are known to give rise to clonal haematopoiesis of intermediate potential (CHIP), a condition linked to age-related haematological malignancies. Despite these insights, the exact roles of circadian rhythms, sphingosine-1-phosphate (S1P), stromal cell-derived factor-1 (SDF-1), sterile inflammation, and the complement cascade on various BM niche cells remain inadequately understood. Further research is needed to elucidate how BM niche cells contribute to these malignancies through neural regulation and their potential in the development of gene-corrected stem cells. This literature review describes the updated functional aspects of BM niche cells in haematopoiesis within the context of haematological malignancies, with a particular focus on neural signaling and the potential of radiomitigators in acute radiation syndrome. Additionally, it underscores the pressing need for technological advancements in stem cell-based therapies to alleviate the impacts of immunological stressors. Recent studies have illuminated the microheterogeneity and temporal stochasticity of niche cells within the BM during haematopoiesis, emphasizing the updated roles of neural signaling and immunosurveillance. The development of gene-corrected stem cells capable of producing blood, immune cells, and tissue-resident progeny is essential for combating age-related haematological malignancies and overcoming immunological challenges. This review aims to provide a comprehensive overview of these evolving insights and their implications for future therapeutic strategies.
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Affiliation(s)
- Narasimha M Beeraka
- Herman B. Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, 1044 W. Walnut Street, R4-168, Indianapolis, IN, 46202, USA.
- Department of Human Anatomy and Histology, I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), 8/2 Trubetskaya Str., Moscow, 119991, Russia.
- Raghavendra Institute of Pharmaceutical Education and Research (RIPER), Anantapuramu, Chiyyedu, Andhra Pradesh, 515721, India.
| | - Basappa Basappa
- Department of Studies in Organic Chemistry, Laboratory of Chemical Biology, University of Mysore, Mysore, Karnataka, 570006, India
| | - Vladimir N Nikolenko
- Department of Human Anatomy and Histology, I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), 8/2 Trubetskaya Str., Moscow, 119991, Russia
| | - P A Mahesh
- Department of Pulmonary Medicine, JSS Medical College, JSS Academy of Higher Education & Research (JSS AHER), Mysuru, Karnataka, India
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Li J, Zhang X, Peng ZX, Chen JH, Liang JH, Ke LQ, Huang D, Cheng WX, Lin S, Li G, Hou R, Zhong WZ, Lin ZJ, Qin L, Chen GQ, Zhang P. Metabolically activated energetic materials mediate cellular anabolism for bone regeneration. Trends Biotechnol 2024; 42:1745-1776. [PMID: 39237385 DOI: 10.1016/j.tibtech.2024.08.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2024] [Revised: 08/01/2024] [Accepted: 08/02/2024] [Indexed: 09/07/2024]
Abstract
The understanding of cellular energy metabolism activation by engineered scaffolds remains limited, posing challenges for therapeutic applications in tissue regeneration. This study presents biosynthesized poly(3-hydroxybutyrate-co-4-hydroxybutyrate) [P(3HB-co-4HB)] and its major degradation product, 3-hydroxybutyrate (3HB), as endogenous bioenergetic fuels that augment cellular anabolism, thereby facilitating the progression of human bone marrow-derived mesenchymal stem cells (hBMSCs) towards osteoblastogenesis. Our research demonstrated that 3HB markedly boosts in vitro ATP production, elevating mitochondrial membrane potential and capillary-like tube formation. Additionally, it raises citrate levels in the tricarboxylic acid (TCA) cycle, facilitating the synthesis of citrate-containing apatite during hBMSCs osteogenesis. Furthermore, 3HB administration significantly increased bone mass in rats with osteoporosis induced by ovariectomy. The findings also showed that P(3HB-co-4HB) scaffold substantially enhances long-term vascularized bone regeneration in rat cranial defect models. These findings reveal a previously unknown role of 3HB in promoting osteogenesis of hBMSCs and highlight the metabolic activation of P(3HB-co-4HB) scaffold for bone regeneration.
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Affiliation(s)
- Jian Li
- Center for Translational Medicine Research and Development, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong 518055, China; Faculty of Biomedical Engineering, Shenzhen University of Advanced Technology, Shenzhen, Guangdong 518055, China.
| | - Xu Zhang
- National Center of Stomatology, National Clinical Research Center for Oral Diseases, National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing Key Laboratory of Digital Stomatology, Center of Digital Dentistry, Peking University School and Hospital of Stomatology, Beijing 100081, China.
| | - Zi-Xin Peng
- Center for Translational Medicine Research and Development, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong 518055, China
| | - Jian-Hai Chen
- Center for Translational Medicine Research and Development, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong 518055, China
| | - Jian-Hui Liang
- Center for Translational Medicine Research and Development, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong 518055, China
| | - Li-Qing Ke
- Center for Translational Medicine Research and Development, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong 518055, China; Faculty of Biomedical Engineering, Shenzhen University of Advanced Technology, Shenzhen, Guangdong 518055, China
| | - Dan Huang
- Center for Translational Medicine Research and Development, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong 518055, China
| | - Wen-Xiang Cheng
- Center for Translational Medicine Research and Development, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong 518055, China; Faculty of Biomedical Engineering, Shenzhen University of Advanced Technology, Shenzhen, Guangdong 518055, China
| | - Sien Lin
- Musculoskeletal Research Laboratory, Department of Orthopedics and Traumatology, The Chinese University of Hong Kong, Hong Kong Special Administrative Region of China
| | - Gang Li
- Musculoskeletal Research Laboratory, Department of Orthopedics and Traumatology, The Chinese University of Hong Kong, Hong Kong Special Administrative Region of China
| | - Rui Hou
- Nam Yue Natural Medicine Co., Ltd., Macau, China
| | | | - Zheng-Jie Lin
- Department of Stomatology, Shenzhen Qianhai Shekou Free Trade Zone Hospital, Shenzhen, Guangdong, 518067, China
| | - Ling Qin
- Musculoskeletal Research Laboratory, Department of Orthopedics and Traumatology, The Chinese University of Hong Kong, Hong Kong Special Administrative Region of China
| | - Guo-Qiang Chen
- School of Life Sciences, Center of Synthetic and Systems Biology, Department of Chemical Engineering, Tsinghua University, Beijing 100084, China.
| | - Peng Zhang
- Center for Translational Medicine Research and Development, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong 518055, China; Faculty of Biomedical Engineering, Shenzhen University of Advanced Technology, Shenzhen, Guangdong 518055, China.
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Liedl EK, van Schoonhoven J, Prommersberger KJ, Mühldorfer-Fodor M. [Focused High-Energy Extracorporeal Shock Wave Therapy (ESWT) for Bone healing Disorders of the Forearm and the Hand]. HANDCHIR MIKROCHIR P 2024; 56:350-358. [PMID: 39333033 DOI: 10.1055/a-2406-5858] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/29/2024] Open
Abstract
BACKGROUND ESWT is a non-surgical treatment option but can also be used in addition to surgical treatment (stabilisation, freshening, defect filling, removal of discomforting osteosynthesis material) for the treatment of delayed bone healing (DBH) and non-union (NU). Its value as well as influencing factors on the upper extremity have not been adequately quantified so far. PATIENTS AND METHODS Sixty cases were retrospectively studied after application of focused high-energy ESWT with regard to healing rate and consolidation time. The influence of age, location, time of treatment and treatment prior to and concurrent with ESWT were analysed. RESULTS In 70% of the cases, healing occurred after a median of 2.4 months (DBH) and 2.8 months (NU). The median age of healed (DBH 44 y., non-union 35 y.) and non-healed (DBH 51 y., NU 37 y.) did not differ significantly. The time between trauma/surgery and ESWT was 4.2 months for DBH in healed and 3.7 months in non-healed without a significant difference, and 27 months for NU in both healed and non-healed. Age and smoking status also had no influence. The healing rate was highest at metacarpal bone/finger/thumb (91%), followed by forearm shaft (88%), epiphysis/metaphysis of the forearm (67%), and, lastly, carpal bones (59%). After conservative pre-treatment, 55% healed, compared with 67% after more than two previous surgeries, 73% without any pre-treatment, and 75% after one previous surgery. Further analysis of surgical pre-treatment showed 85% healing after ORIF alone, 64% without previous surgery, and 57% healing after ORIF with bone grafting/debridement. Intraoperative ESWT combined with bone debridement/transplantation and ORIF resulted in 67% healing, compared with 86% in combination with ORIF alone. ESWT alone or with only minimal measures (removal of osteosynthesis material) led to 70% consolidation. CONCLUSION ESWT is equally effective at any stage of a bone healing disorder. The principles of stability and filling of bone defects must also be taken into account when using ESWT; then ESWT alone or combined with surgery is equally effective. The negative influence of bone defects/resorption is still detectable even with ESWT. Furthermore, treatment of the scaphoid is more problematic compared with other locations. Previous surgery is not a negative factor, even with osteosynthesis material in situ.
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Affiliation(s)
- Eva-Kristina Liedl
- Klinik für Handchirurgie, Rhön Klinikum Campus Bad Neustadt, Bad Neustadt, Germany
| | - Jörg van Schoonhoven
- Klinik für Handchirurgie, Rhön Klinikum Campus Bad Neustadt, Bad Neustadt, Germany
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Kou D, Chen Q, Wang Y, Xu G, Lei M, Tang X, Ni H, Zhang F. The application of extracorporeal shock wave therapy on stem cells therapy to treat various diseases. Stem Cell Res Ther 2024; 15:271. [PMID: 39183302 PMCID: PMC11346138 DOI: 10.1186/s13287-024-03888-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Accepted: 08/16/2024] [Indexed: 08/27/2024] Open
Abstract
In the last ten years, stem cell (SC) therapy has been extensively used to treat a range of conditions such as degenerative illnesses, ischemia-related organ dysfunction, diabetes, and neurological disorders. However, the clinical application of these therapies is limited due to the poor survival and differentiation potential of stem cells (SCs). Extracorporeal shock wave therapy (ESWT), as a non-invasive therapy, has shown great application potential in enhancing the proliferation, differentiation, migration, and recruitment of stem cells, offering new possibilities for utilizing ESWT in conjunction with stem cells for the treatment of different systemic conditions. The review provides a detailed overview of the advances in using ESWT with SCs to treat musculoskeletal, cardiovascular, genitourinary, and nervous system conditions, suggesting that ESWT is a promising strategy for enhancing the efficacy of SC therapy for various diseases.
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Affiliation(s)
- Dongyan Kou
- Department of Rehabilitation Medicine, CNPC Central Hospital, Langfang, 065000, PR China
| | - Qingyu Chen
- Department of Rehabilitation Medicine, CNPC Central Hospital, Langfang, 065000, PR China
| | - Yujing Wang
- Department of Rehabilitation Medicine, CNPC Central Hospital, Langfang, 065000, PR China
| | - Guangyu Xu
- Department of Rehabilitation Medicine, The Third Hospital of Hebei Medical University, No. 139 Ziqiang Road, Shijiazhuang, Hebei, 050051, PR China
| | - Mingcheng Lei
- Department of Rehabilitation Medicine, The Third Hospital of Hebei Medical University, No. 139 Ziqiang Road, Shijiazhuang, Hebei, 050051, PR China
| | - Xiaobin Tang
- Department of Rehabilitation Medicine, CNPC Central Hospital, Langfang, 065000, PR China
| | - Hongbin Ni
- Department of Neurosurgery, Nanjing University Medical School Affiliated Nanjing Drum Tower Hospital, 321 Zhongshan Road, Nanjing, Jiangsu, 210008, China.
| | - Feng Zhang
- Department of Rehabilitation Medicine, The Third Hospital of Hebei Medical University, No. 139 Ziqiang Road, Shijiazhuang, Hebei, 050051, PR China.
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Müller WEG, Neufurth M, Wang S, Schröder HC, Wang X. Polyphosphate Nanoparticles: Balancing Energy Requirements in Tissue Regeneration Processes. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2024; 20:e2309528. [PMID: 38470207 DOI: 10.1002/smll.202309528] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/20/2023] [Revised: 01/29/2024] [Indexed: 03/13/2024]
Abstract
Nanoparticles of a particular, evolutionarily old inorganic polymer found across the biological kingdoms have attracted increasing interest in recent years not only because of their crucial role in metabolism but also their potential medical applicability: it is inorganic polyphosphate (polyP). This ubiquitous linear polymer is composed of 10-1000 phosphate residues linked by high-energy anhydride bonds. PolyP causes induction of gene activity, provides phosphate for bone mineralization, and serves as an energy supplier through enzymatic cleavage of its acid anhydride bonds and subsequent ATP formation. The biomedical breakthrough of polyP came with the development of a successful fabrication process, in depot form, as Ca- or Mg-polyP nanoparticles, or as the directly effective polymer, as soluble Na-polyP, for regenerative repair and healing processes, especially in tissue areas with insufficient blood supply. Physiologically, the platelets are the main vehicles for polyP nanoparticles in the circulating blood. To be biomedically active, these particles undergo coacervation. This review provides an overview of the properties of polyP and polyP nanoparticles for applications in the regeneration and repair of bone, cartilage, and skin. In addition to studies on animal models, the first successful proof-of-concept studies on humans for the healing of chronic wounds are outlined.
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Affiliation(s)
- Werner E G Müller
- ERC Advanced Investigator Grant Research Group at the Institute for Physiological Chemistry, University Medical Center of the Johannes Gutenberg University, Duesbergweg 6, D-55128, Mainz, Germany
| | - Meik Neufurth
- ERC Advanced Investigator Grant Research Group at the Institute for Physiological Chemistry, University Medical Center of the Johannes Gutenberg University, Duesbergweg 6, D-55128, Mainz, Germany
| | - Shunfeng Wang
- ERC Advanced Investigator Grant Research Group at the Institute for Physiological Chemistry, University Medical Center of the Johannes Gutenberg University, Duesbergweg 6, D-55128, Mainz, Germany
| | - Heinz C Schröder
- ERC Advanced Investigator Grant Research Group at the Institute for Physiological Chemistry, University Medical Center of the Johannes Gutenberg University, Duesbergweg 6, D-55128, Mainz, Germany
| | - Xiaohong Wang
- ERC Advanced Investigator Grant Research Group at the Institute for Physiological Chemistry, University Medical Center of the Johannes Gutenberg University, Duesbergweg 6, D-55128, Mainz, Germany
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Bessa-Andrês C, Pinto-Cardoso R, Tarasova K, Pereira-Gonçalves AL, Gaio-Ferreira-Castro JM, Carvalho LS, Costa MA, Ferreirinha F, Canadas-Sousa A, Marinhas J, Freitas R, Lemos R, Vilaça A, Oliveira A, Correia-de-Sá P, Noronha-Matos JB. Mechanical stimulation-induced purinome priming fosters osteogenic differentiation and osteointegration of mesenchymal stem cells from the bone marrow of post-menopausal women. Stem Cell Res Ther 2024; 15:168. [PMID: 38886849 PMCID: PMC11184869 DOI: 10.1186/s13287-024-03775-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Accepted: 05/27/2024] [Indexed: 06/20/2024] Open
Abstract
BACKGROUND Mechanical stimulation (MS) significantly increases the release of adenine and uracil nucleotides from bone marrow-derived mesenchymal stem cells (BM-MSCs) undergoing osteogenic differentiation. Released nucleotides acting via ionotropic P2X7 and metabotropic P2Y6 purinoceptors sensitive to ATP and UDP, respectively, control the osteogenic commitment of BM-MSCs and, thus, bone growth and remodelling. Yet, this mechanism is impaired in post-menopausal (Pm)-derived BM-MSCs, mostly because NTPDase3 overexpression decreases the extracellular accumulation of nucleotides below the levels required to activate plasma membrane-bound P2 purinoceptors. This prompted us to investigate whether in vitro MS of BM-MSCs from Pm women could rehabilitate their osteogenic commitment and whether xenotransplantation of MS purinome-primed Pm cells promote repair of critical bone defects in an in vivo animal model. METHODS BM-MSCs were harvested from the neck of femora of Pm women (70 ± 3 years old) undergoing total hip replacement. The cells grew, for 35 days, in an osteogenic-inducing medium either submitted (SS) or not (CTR) to MS (90 r.p.m. for 30 min) twice a week. Increases in alkaline phosphatase activity and in the amount of osteogenic transcription factors, osterix and osteopontin, denoted osteogenic cells differentiation, while bone nodules formation was ascertain by the alizarin red-staining assay. The luciferin-luciferase bioluminescence assay was used to quantify extracellular ATP. The kinetics of the extracellular ATP (100 µM) and UDP (100 µM) catabolism was assessed by HPLC. The density of P2Y6 and P2X7 purinoceptors in the cells was assessed by immunofluorescence confocal microscopy. MS-stimulated BM-MSCs from Pm women were xenotransplanted into critical bone defects drilled in the great trochanter of femora of one-year female Wistar rats; bone repair was assessed by histological analysis 10 days after xenotransplantation. RESULTS MS-stimulated Pm BM-MSCs in culture (i) release 1.6-fold higher ATP amounts, (ii) overexpress P2X7 and P2Y6 purinoceptors, (iii) exhibit higher alkaline phosphatase activity and overexpress the osteogenic transcription factors, osterix and osteopontin, and (iv) form larger bone nodules, than CTR cells. Selective blockage of P2X7 and P2Y6 purinoceptors with A438079 (3 µM) and MRS 2578 (0.1 µM), respectively, prevented the osteogenic commitment of cultured Pm BM-MSCs. Xenotransplanted MS purinome-primed Pm BM-MSCs accelerated the repair of critical bone defects in the in vivo rat model. CONCLUSIONS Data suggest that in vitro MS restores the purinergic cell-to-cell communication fostering the osteogenic differentiation and osteointegration of BM-MSCs from Pm women, a strategy that may be used in bone regeneration and repair tactics.
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Affiliation(s)
- Catarina Bessa-Andrês
- Laboratório de Farmacologia e Neurobiologia, Instituto de Ciências Biomédicas Abel Salazar - Universidade do Porto (ICBAS-UP), Porto, 4050-313, Portugal
- Center for Drug Discovery and Innovative Medicines (MedInUP), Instituto de Ciências Biomédicas Abel Salazar - Universidade do Porto (ICBAS-UP), Porto, 4050-313, Portugal
| | - Rui Pinto-Cardoso
- Laboratório de Farmacologia e Neurobiologia, Instituto de Ciências Biomédicas Abel Salazar - Universidade do Porto (ICBAS-UP), Porto, 4050-313, Portugal
- Center for Drug Discovery and Innovative Medicines (MedInUP), Instituto de Ciências Biomédicas Abel Salazar - Universidade do Porto (ICBAS-UP), Porto, 4050-313, Portugal
| | - Karyna Tarasova
- Laboratório de Farmacologia e Neurobiologia, Instituto de Ciências Biomédicas Abel Salazar - Universidade do Porto (ICBAS-UP), Porto, 4050-313, Portugal
- Center for Drug Discovery and Innovative Medicines (MedInUP), Instituto de Ciências Biomédicas Abel Salazar - Universidade do Porto (ICBAS-UP), Porto, 4050-313, Portugal
| | - Ana Luísa Pereira-Gonçalves
- Laboratório de Farmacologia e Neurobiologia, Instituto de Ciências Biomédicas Abel Salazar - Universidade do Porto (ICBAS-UP), Porto, 4050-313, Portugal
- Center for Drug Discovery and Innovative Medicines (MedInUP), Instituto de Ciências Biomédicas Abel Salazar - Universidade do Porto (ICBAS-UP), Porto, 4050-313, Portugal
| | - Joana Maria Gaio-Ferreira-Castro
- Laboratório de Farmacologia e Neurobiologia, Instituto de Ciências Biomédicas Abel Salazar - Universidade do Porto (ICBAS-UP), Porto, 4050-313, Portugal
- Center for Drug Discovery and Innovative Medicines (MedInUP), Instituto de Ciências Biomédicas Abel Salazar - Universidade do Porto (ICBAS-UP), Porto, 4050-313, Portugal
| | - Liliana S Carvalho
- Laboratório de Farmacologia e Neurobiologia, Instituto de Ciências Biomédicas Abel Salazar - Universidade do Porto (ICBAS-UP), Porto, 4050-313, Portugal
- Center for Drug Discovery and Innovative Medicines (MedInUP), Instituto de Ciências Biomédicas Abel Salazar - Universidade do Porto (ICBAS-UP), Porto, 4050-313, Portugal
| | - Maria Adelina Costa
- Laboratório de Farmacologia e Neurobiologia, Instituto de Ciências Biomédicas Abel Salazar - Universidade do Porto (ICBAS-UP), Porto, 4050-313, Portugal
- Center for Drug Discovery and Innovative Medicines (MedInUP), Instituto de Ciências Biomédicas Abel Salazar - Universidade do Porto (ICBAS-UP), Porto, 4050-313, Portugal
- Departamento de Química, Instituto de Ciências Biomédicas Abel Salazar - Universidade do Porto (ICBAS-UP), Porto, 4050-313, Portugal
| | - Fátima Ferreirinha
- Laboratório de Farmacologia e Neurobiologia, Instituto de Ciências Biomédicas Abel Salazar - Universidade do Porto (ICBAS-UP), Porto, 4050-313, Portugal
- Center for Drug Discovery and Innovative Medicines (MedInUP), Instituto de Ciências Biomédicas Abel Salazar - Universidade do Porto (ICBAS-UP), Porto, 4050-313, Portugal
| | - Ana Canadas-Sousa
- Departamento de Patologia e Imunologia Molecular, Instituto de Ciências Biomédicas Abel Salazar - Universidade do Porto (ICBAS-UP), Porto, 4050-313, Portugal
| | - José Marinhas
- Serviço de Ortopedia e Traumatologia, Centro Hospitalar de Vila Nova de Gaia - Espinho, Vila Nova de Gaia, 4434-502, Portugal
| | - Rolando Freitas
- Serviço de Ortopedia e Traumatologia, Centro Hospitalar de Vila Nova de Gaia - Espinho, Vila Nova de Gaia, 4434-502, Portugal
| | - Rui Lemos
- Serviço de Ortopedia e Traumatologia, Centro Hospitalar de Vila Nova de Gaia - Espinho, Vila Nova de Gaia, 4434-502, Portugal
| | - Adélio Vilaça
- Serviço de Ortopedia, Centro Hospitalar Universitário de Santo António, Porto, 4099-001, Portugal
| | - António Oliveira
- Serviço de Ortopedia, Centro Hospitalar Universitário de Santo António, Porto, 4099-001, Portugal
| | - Paulo Correia-de-Sá
- Laboratório de Farmacologia e Neurobiologia, Instituto de Ciências Biomédicas Abel Salazar - Universidade do Porto (ICBAS-UP), Porto, 4050-313, Portugal.
- Center for Drug Discovery and Innovative Medicines (MedInUP), Instituto de Ciências Biomédicas Abel Salazar - Universidade do Porto (ICBAS-UP), Porto, 4050-313, Portugal.
| | - José Bernardo Noronha-Matos
- Laboratório de Farmacologia e Neurobiologia, Instituto de Ciências Biomédicas Abel Salazar - Universidade do Porto (ICBAS-UP), Porto, 4050-313, Portugal.
- Center for Drug Discovery and Innovative Medicines (MedInUP), Instituto de Ciências Biomédicas Abel Salazar - Universidade do Porto (ICBAS-UP), Porto, 4050-313, Portugal.
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10
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Wikarska A, Roszak K, Roszek K. Mesenchymal Stem Cells and Purinergic Signaling in Autism Spectrum Disorder: Bridging the Gap between Cell-Based Strategies and Neuro-Immune Modulation. Biomedicines 2024; 12:1310. [PMID: 38927517 PMCID: PMC11201695 DOI: 10.3390/biomedicines12061310] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2024] [Revised: 05/26/2024] [Accepted: 06/11/2024] [Indexed: 06/28/2024] Open
Abstract
The prevalence of autism spectrum disorder (ASD) is still increasing, which means that this neurodevelopmental lifelong pathology requires special scientific attention and efforts focused on developing novel therapeutic approaches. It has become increasingly evident that neuroinflammation and dysregulation of neuro-immune cross-talk are specific hallmarks of ASD, offering the possibility to treat these disorders by factors modulating neuro-immunological interactions. Mesenchymal stem cell-based therapy has already been postulated as one of the therapeutic approaches for ASD; however, less is known about the molecular mechanisms of stem cell influence. One of the possibilities, although still underestimated, is the paracrine purinergic activity of MSCs, by which stem cells ameliorate inflammatory reactions. Modulation of adenosine signaling may help restore neurotransmitter balance, reduce neuroinflammation, and improve overall brain function in individuals with ASD. In our review article, we present a novel insight into purinergic signaling, including but not limited to the adenosinergic pathway and its role in neuroinflammation and neuro-immune cross-talk modulation. We anticipate that by achieving a greater understanding of the purinergic signaling contribution to ASD and related disorders, novel therapeutic strategies may be devised for patients with autism in the near future.
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Affiliation(s)
| | | | - Katarzyna Roszek
- Department of Biochemistry, Faculty of Biological and Veterinary Sciences, Nicolaus Copernicus University in Torun, Lwowska 1, 87-100 Torun, Poland; (A.W.); (K.R.)
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11
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Sun X, Li Z, Wang X, He J, Wu Y. Inorganic Phosphate as "Bioenergetic Messenger" Triggers M2-Type Macrophage Polarization. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2306062. [PMID: 38247159 PMCID: PMC10987138 DOI: 10.1002/advs.202306062] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/28/2023] [Revised: 01/12/2024] [Indexed: 01/23/2024]
Abstract
The effects of calcium phosphate (CaP) materials on macrophage polarization state vary with their physicochemical properties. The study aims to elucidate the impact of phosphate ion-mediated energy metabolism on M2 macrophage polarization and the corresponding regulatory mechanism. The phosphate ions released from CaP ceramic as bioenergetic factor is identified; its concentration is closely associated with the polarized state. After being taken up by the sodium-dependent phosphate transporter 1, extracellular phosphate ions produce energy via oxidative phosphorylation by facilitating tricarboxylic acid flux, thereby contributing to M2 macrophage polarization. Further mechanistic analysis reveals that the elevation of the bioenergetic basis can drive macrophage M2 polarization via the AMP-activated protein kinase-mammalian target of rapamycin (AMPK-mTOR) axis. Another regulatory effect is that of the adenosine triphosphate (ATP), a signaling molecule. Intracellular ATP is released into the extracellular space and degraded to adenosine, which serves as a signaling molecule through the A2b adenosine receptor to activate the cyclic adenosine monophosphate (cAMP) pathway, thereby promoting M2 macrophage polarization. Overall, these findings may transform the existing knowledge on cell metabolism and energy homeostasis from bystanders to pivotal factors guiding M2 macrophage polarization and have implications for the future design of biomimetic CaP scaffolds.
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Affiliation(s)
- Xiaoqing Sun
- National Engineering Research Center for BiomaterialsSichuan UniversityChengduSichuan610064P. R. China
| | - Zhiyu Li
- National Engineering Research Center for BiomaterialsSichuan UniversityChengduSichuan610064P. R. China
| | - Xiang Wang
- National Engineering Research Center for BiomaterialsSichuan UniversityChengduSichuan610064P. R. China
| | - Jing He
- National Engineering Research Center for BiomaterialsSichuan UniversityChengduSichuan610064P. R. China
| | - Yao Wu
- National Engineering Research Center for BiomaterialsSichuan UniversityChengduSichuan610064P. R. China
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12
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Li J, Li H, Bi S, Sun Y, Gu F, Yu T. Shock wave assisted intracellular delivery of antibiotics against bone infection with Staphylococcus aureus via P2X7 receptors. J Orthop Translat 2024; 45:10-23. [PMID: 38434180 PMCID: PMC10904912 DOI: 10.1016/j.jot.2023.10.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Accepted: 10/20/2023] [Indexed: 03/05/2024] Open
Abstract
Background Treatment of chronic osteomyelitis (bone infection) remains a clinical challenge; in particular, it requires enhanced delivery of antibiotic drugs for the treatment of intracellular Staphylococcus aureus (S. aureus), which prevents infection recurrence and resistance. Previous studies have found that noninvasive shock waves used to treat musculoskeletal diseases can alter cell permeability, however, it is unclear whether shock waves alter cell membrane permeability in chronic osteomyelitis. Furthermore, it remains unknown whether such changes in permeability promote the entry of antibiotics into osteoblasts to exert antibacterial effects. Methods In our study, trypan blue staining was used to determine the shock wave parameters that had no obvious damage to the osteoblast model; the effect of shocks waves on the cell membrane permeability of osteoblast model was detected by BODIPY®FL vancomycin; high performance liquid chromatography-mass spectrometry (HLPC-MS) was used to detect the effect of shock wave on the entry of antibiotics into the osteoblast model; plate colony counting method was used to detect the clearance effect of shock wave assisted antibiotics on S. aureus in the osteoblast model. To explore the mechanism, the effect of different pulses of shock waves on S. aureus was examined by plate colony counting method, besides, P2X7 receptor in osteoblast was detected by immunofluorescence and the extracellular ATP levels was detected. Furthermore, the effect of P2X7 receptor antagonists KN-62 or A740003 on the intracellular antibacterial activity of shock-assisted antibiotics was observed. Then, we used S. aureus to establish a rat model of chronic tibial osteomyelitis and investigated the efficacy and safety of shock-wave assisted antibiotics in the treatment of chronic osteomyelitis in rats. Results The viability of the osteoblast models of intracellular S. aureus infection was not significantly affected by the application of up to 400 shock wave pulses at 0.21 mJ/mm2. Surprisingly, the delivery of BODIPY®FL vancomycin to osteoblast model cells was markedly enhanced by this shock wave treatment. Furthermore, the shock wave therapy increased the delivery of hydrophilic antibiotics (vancomycin and cefuroxime sodium), but not lipophilic antibiotics (rifampicin and levofloxacin), which improved the intracellular antibacterial effect. Afterwards, we discovered that shock wave treatment increased the extracellular concentration of ATP (the P2X7 receptor activator)， while KN-62 or A740003, a P2X7 receptor inhibitor, decreased intracellular antibacterial activity. We then found that 0.1 mL of 1 × 1011 CFU/mL ATCC25923 S. aureus was suitable for modeling chronic osteomyelitis in rats. Besides, the shock wave-assisted vancomycin treatment with the strongest antibacterial and osteogenic effects among the tested treatments was confirmed in vivo by imaging examination, microbiological cultures, and histopathology, with favorable safety. Conclusions Our results suggest that shock waves can promote the entry of antibiotics into osteoblasts for antibacteria by changing the cell membrane permeability in a P2X7 receptor-dependent manner. Besides, considering antibacterial and osteogenic efficiency and a high degree of safety in rat osteomyelitis model, shock wave-assisted vancomycin treatment may thus represent a possible adjuvant therapy for chronic osteomyelitis.
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Affiliation(s)
- Jiangbi Li
- Department of Orthopedics , Orthopaedic Center, The First Hospital of Jilin University, Changchun, Jilin, China
- Department of Orthopaedics, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Haixia Li
- Department of Neurology, The Affiliated Hospital of Kunming University of Science and Technology, the First People's Hospital of Yunnan Province, Kunming, Yunnan, China
| | - Songqi Bi
- Department of Orthopedics , Orthopaedic Center, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Yang Sun
- Department of Orthopedics , Orthopaedic Center, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Feng Gu
- Department of Orthopedics , The Second Hospital of Jilin University, Changchun, Jilin, China
| | - Tiecheng Yu
- Department of Orthopedics , Orthopaedic Center, The First Hospital of Jilin University, Changchun, Jilin, China
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13
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Singh P, Singh M, Singh B, Sharma K, Kumar N, Singh D, Klair HS, Mastana S. Implications of siRNA Therapy in Bone Health: Silencing Communicates. Biomedicines 2024; 12:90. [PMID: 38255196 PMCID: PMC10813040 DOI: 10.3390/biomedicines12010090] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Revised: 12/27/2023] [Accepted: 12/28/2023] [Indexed: 01/24/2024] Open
Abstract
The global statistics of bone disorders, skeletal defects, and fractures are frightening. Several therapeutic strategies are being used to fix them; however, RNAi-based siRNA therapy is starting to prove to be a promising approach for the prevention of bone disorders because of its advanced capabilities to deliver siRNA or siRNA drug conjugate to the target tissue. Despite its 'bench-to-bedside' usefulness and approval by food and drug administration for five siRNA-based therapeutic medicines: Patisiran, Vutrisiran, Inclisiran, Lumasiran, and Givosiran, its use for the other diseases still remains to be resolved. By correcting the complications and complexities involved in siRNA delivery for its sustained release, better absorption, and toxicity-free activity, siRNA therapy can be harnessed as an experimental tool for the prevention of complex and undruggable diseases with a personalized medicine approach. The present review summarizes the findings of notable research to address the implications of siRNA in bone health for the restoration of bone mass, recovery of bone loss, and recuperation of bone fractures.
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Affiliation(s)
- Puneetpal Singh
- Department of Human Genetics, Punjabi University, Patiala 147002, Punjab, India; (M.S.); (B.S.); (K.S.); (N.K.)
| | - Monica Singh
- Department of Human Genetics, Punjabi University, Patiala 147002, Punjab, India; (M.S.); (B.S.); (K.S.); (N.K.)
| | - Baani Singh
- Department of Human Genetics, Punjabi University, Patiala 147002, Punjab, India; (M.S.); (B.S.); (K.S.); (N.K.)
| | - Kirti Sharma
- Department of Human Genetics, Punjabi University, Patiala 147002, Punjab, India; (M.S.); (B.S.); (K.S.); (N.K.)
| | - Nitin Kumar
- Department of Human Genetics, Punjabi University, Patiala 147002, Punjab, India; (M.S.); (B.S.); (K.S.); (N.K.)
| | - Deepinder Singh
- Vardhman Mahavir Health Care, Urban Estate, Ph-II, Patiala 147002, Punjab, India
| | | | - Sarabjit Mastana
- Human Genomics Laboratory, School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough LE11 3TU, UK
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14
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Pinto-Cardoso R, Bessa-Andrês C, Correia-de-Sá P, Bernardo Noronha-Matos J. Could hypoxia rehabilitate the osteochondral diseased interface? Lessons from the interplay of hypoxia and purinergic signals elsewhere. Biochem Pharmacol 2023:115646. [PMID: 37321413 DOI: 10.1016/j.bcp.2023.115646] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2023] [Revised: 06/03/2023] [Accepted: 06/07/2023] [Indexed: 06/17/2023]
Abstract
The osteochondral unit comprises the articular cartilage (90%), subchondral bone (5%) and calcified cartilage (5%). All cells present at the osteochondral unit that is ultimately responsible for matrix production and osteochondral homeostasis, such as chondrocytes, osteoblasts, osteoclasts and osteocytes, can release adenine and/or uracil nucleotides to the local microenvironment. Nucleotides are released by these cells either constitutively or upon plasma membrane damage, mechanical stress or hypoxia conditions. Once in the extracellular space, endogenously released nucleotides can activate membrane-bound purinoceptors. Activation of these receptors is fine-tuning regulated by nucleotides' breakdown by enzymes of the ecto-nucleotidase cascade. Depending on the pathophysiological conditions, both the avascular cartilage and the subchondral bone subsist to significant changes in oxygen tension, which has a tremendous impact on tissue homeostasis. Cell stress due to hypoxic conditions directly influences the expression and activity of several purinergic signalling players, namely nucleotide release channels (e.g. Cx43), NTPDase enzymes and purinoceptors. This review gathers experimental evidence concerning the interplay between hypoxia and the purinergic signalling cascade contributing to osteochondral unit homeostasis. Reporting deviations to this relationship resulting from pathological alterations of articular joints may ultimately unravel novel therapeutic targets for osteochondral rehabilitation. At this point, one can only hypothesize how hypoxia mimetic conditions can be beneficial to the ex vivo expansion and differentiation of osteo- and chondro-progenitors for auto-transplantation and tissue regenerative purposes.
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Affiliation(s)
- Rui Pinto-Cardoso
- Laboratório de Farmacologia e Neurobiologia; Center for Drug Discovery and Innovative Medicines (MedInUP), Departamento de Imuno-Fisiologia e Farmacologia, Instituto de Ciências Biomédicas Abel Salazar - Universidade do Porto (ICBAS-UP)
| | - Catarina Bessa-Andrês
- Laboratório de Farmacologia e Neurobiologia; Center for Drug Discovery and Innovative Medicines (MedInUP), Departamento de Imuno-Fisiologia e Farmacologia, Instituto de Ciências Biomédicas Abel Salazar - Universidade do Porto (ICBAS-UP)
| | - Paulo Correia-de-Sá
- Laboratório de Farmacologia e Neurobiologia; Center for Drug Discovery and Innovative Medicines (MedInUP), Departamento de Imuno-Fisiologia e Farmacologia, Instituto de Ciências Biomédicas Abel Salazar - Universidade do Porto (ICBAS-UP)
| | - José Bernardo Noronha-Matos
- Laboratório de Farmacologia e Neurobiologia; Center for Drug Discovery and Innovative Medicines (MedInUP), Departamento de Imuno-Fisiologia e Farmacologia, Instituto de Ciências Biomédicas Abel Salazar - Universidade do Porto (ICBAS-UP).
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15
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Huang H, He YM, Lin MM, Wang Y, Zhang X, Liang L, He X. P2X7Rs: new therapeutic targets for osteoporosis. Purinergic Signal 2023; 19:207-219. [PMID: 35106736 PMCID: PMC9984661 DOI: 10.1007/s11302-021-09836-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Accepted: 12/17/2021] [Indexed: 02/05/2023] Open
Abstract
Increasing evidence suggests that both the occurrence and progression of osteoporosis are associated with inflammation, especially in primary osteoporosis. The maintenance of skeletal homeostasis is dependent on the complex regulation of bone metabolism. Numerous evidence suggested that purinoceptor networks are essential for bone homeostasis. In this review, the relationship between inflammation and the development of osteoporosis and the role of P2X7 receptor (P2X7R) in regulating the dynamic regulation of bone reconstruction were covered. We also discussed how P2X7R regulates the balance between resorption and bone formation by osteoblasts and reviewed the relevance of P2X7R polymorphisms in skeletal physiology. Finally, we analyzed potential targets of P2X7R for osteoporosis.
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Affiliation(s)
- Haoyun Huang
- Clinical Medical School, Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, China
| | - Yu-Mei He
- School of Sports Medicine and Health, Chengdu Sports University, Chengdu, 610041, China
| | - Miao-Miao Lin
- School of Sports Medicine and Health, Chengdu Sports University, Chengdu, 610041, China
| | - Yanchao Wang
- Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Xiaomei Zhang
- Laboratory Animal Center of Sichuan University, Chengdu, 610041, China
| | - Li Liang
- Institute of Biomedical Engineering, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, 610041, China
| | - Xueling He
- Laboratory Animal Center of Sichuan University, Chengdu, 610041, China.
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16
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Chaudhary S, Ghosal D, Tripathi P, Kumar S. Cellular metabolism: a link connecting cellular behaviour with the physiochemical properties of biomaterials for bone tissue engineering. Biomater Sci 2023; 11:2277-2291. [PMID: 36748852 DOI: 10.1039/d2bm01410f] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
Biomaterial properties, such as surface roughness, morphology, stiffness, conductivity, and chemistry, significantly influence a cell's ability to sense and adhere to its surface and regulate cell functioning. Understanding how biomaterial properties govern changes in cellular function is one of the fundamental goals of tissue engineering. Still, no generalized rule is established to predict cellular processes (adhesion, spreading, growth and differentiation) on biomaterial surfaces. A few studies have highlighted that cells sense biomaterial properties at multiple length scales and regulate various intracellular biochemical processes like cytoskeleton organization, gene regulation, and receptor expression to influence cell function. However, recent studies have found cellular metabolism as another critical aspect of cellular processes that regulate cell behavior, co-relating metabolism to cellular functions like adhesion, proliferation, and differentiation. Now researchers have started to uncover previously overlooked factors on how biomaterial properties govern changes in cellular functions mediated through metabolism. This review highlights how different physiochemical properties of scaffolds designed from different biomaterials influence cell metabolism. The review also discusses the role of metabolism change in cellular functions and cell behavior in the context of bone tissue engineering. It also emphasizes the importance of cell metabolism as a missing link between the cellular behavior and physicochemical properties of scaffolds and serves as a guiding principle for designing scaffolds for tissue engineering.
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Affiliation(s)
- Shivani Chaudhary
- Centre for Biomedical Engineering, Indian Institute of Technology Delhi, New Delhi 110016, India.
| | - Doyel Ghosal
- Centre for Biomedical Engineering, Indian Institute of Technology Delhi, New Delhi 110016, India.
| | - Pravesh Tripathi
- Centre for Biomedical Engineering, Indian Institute of Technology Delhi, New Delhi 110016, India.
| | - Sachin Kumar
- Centre for Biomedical Engineering, Indian Institute of Technology Delhi, New Delhi 110016, India. .,Department of Biomedical Engineering, All India Institute of Medical Sciences, New Delhi 110029, India
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17
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Chen M, Li M, Wei Y, Xue C, Chen M, Fei Y, Tan L, Luo Z, Cai K, Hu Y. ROS-activatable biomimetic interface mediates in-situ bioenergetic remodeling of osteogenic cells for osteoporotic bone repair. Biomaterials 2022; 291:121878. [DOI: 10.1016/j.biomaterials.2022.121878] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Revised: 10/18/2022] [Accepted: 10/23/2022] [Indexed: 11/06/2022]
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18
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Dsouza C, Moussa MS, Mikolajewicz N, Komarova SV. Extracellular ATP and its derivatives provide spatiotemporal guidance for bone adaptation to wide spectrum of physical forces. Bone Rep 2022; 17:101608. [PMID: 35992507 PMCID: PMC9385560 DOI: 10.1016/j.bonr.2022.101608] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Revised: 07/27/2022] [Accepted: 07/29/2022] [Indexed: 11/17/2022] Open
Abstract
ATP is a ubiquitous intracellular molecule critical for cellular bioenergetics. ATP is released in response to mechanical stimulation through vesicular release, small tears in cellular plasma membranes, or when cells are destroyed by traumatic forces. Extracellular ATP is degraded by ecto-ATPases to form ADP and eventually adenosine. ATP, ADP, and adenosine signal through purinergic receptors, including seven P2X ATP-gated cation channels, seven G-protein coupled P2Y receptors responsive to ATP and ADP, and four P1 receptors stimulated by adenosine. The goal of this review is to build a conceptual model of the role of different components of this complex system in coordinating cellular responses that are appropriate to the degree of mechanical stimulation, cell proximity to the location of mechanical injury, and time from the event. We propose that route and amount of ATP release depend on the scale of mechanical forces, ranging from vesicular release of small ATP boluses upon membrane deformation, to leakage of ATP through resealable plasma membrane tears, to spillage of cellular content due to destructive forces. Correspondingly, different P2 receptors responsive to ATP will be activated according to their affinity at the site of mechanical stimulation. ATP is a small molecule that readily diffuses through the environment, bringing the signal to the surrounding cells. ATP is also degraded to ADP which can stimulate a distinct set of P2 receptors. We propose that depending on the magnitude of mechanical forces and distance from the site of their application, ATP/ADP profiles will be different, allowing the relay of information about tissue level injury and proximity. Lastly, ADP is degraded to adenosine acting via its P1 receptors. The presence of large amounts of adenosine without ATP, indicates that an active source of ATP release is no longer present, initiating the transition to the recovery phase. This model consolidates the knowledge regarding the individual components of the purinergic system into a conceptual framework of choreographed responses to physical forces.
Cellular bioenergetic molecule ATP is released when cell is mechanically stimulated. ATP release is proportional to the amount of cellular damage. ATP diffusion and transformation to ADP indicates the proximity to the damage. Purinergic receptors form a network choreographing cell response to physical forces. Complete transformation of ATP to adenosine initiates the recovery phase.
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Affiliation(s)
- Chrisanne Dsouza
- Department of Experimental Surgery, McGill University, Montreal, QC H3G 1A4, Canada
- Shriners Hospitals for Children- Canada, Montreal, QC H4A 0A9, Canada
| | - Mahmoud S. Moussa
- Shriners Hospitals for Children- Canada, Montreal, QC H4A 0A9, Canada
- Faculty of Dental Medicine and Oral Health Sciences, McGill University, Montreal, QC H3A 1G1, Canada
| | - Nicholas Mikolajewicz
- Shriners Hospitals for Children- Canada, Montreal, QC H4A 0A9, Canada
- Faculty of Dental Medicine and Oral Health Sciences, McGill University, Montreal, QC H3A 1G1, Canada
| | - Svetlana V. Komarova
- Department of Experimental Surgery, McGill University, Montreal, QC H3G 1A4, Canada
- Shriners Hospitals for Children- Canada, Montreal, QC H4A 0A9, Canada
- Faculty of Dental Medicine and Oral Health Sciences, McGill University, Montreal, QC H3A 1G1, Canada
- Corresponding author.
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19
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Ryskalin L, Morucci G, Natale G, Soldani P, Gesi M. Molecular Mechanisms Underlying the Pain-Relieving Effects of Extracorporeal Shock Wave Therapy: A Focus on Fascia Nociceptors. Life (Basel) 2022; 12:life12050743. [PMID: 35629410 PMCID: PMC9146519 DOI: 10.3390/life12050743] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Revised: 05/14/2022] [Accepted: 05/15/2022] [Indexed: 12/11/2022] Open
Abstract
In recent years, extracorporeal shock wave therapy (ESWT) has received increasing attention for its potential beneficial effects on various bone and soft-tissue pathologies, yielding promising outcomes for pain relief and functional recovery. In fact, ESWT has emerged as an alternative, non-invasive, and safe treatment for the management of numerous musculoskeletal disorders, including myofascial pain syndrome (MPS). In particular, MPS is a common chronic painful condition, accounting for the largest proportion of patients affected by musculoskeletal problems. Remarkably, sensory innervation and nociceptors of the fascial system are emerging to play a pivotal role as pain generators in MPS. At the same time, increasing evidence demonstrates that application of ESWT results in selective loss of sensory unmyelinated nerve fibers, thereby inducing long-lasting analgesia. The findings discussed in the present review are supposed to add novel viewpoints that may further enrich our knowledge on the complex interactions occurring between disorders of the deep fascia including changes in innervation, sensitization of fascial nociceptors, the pathophysiology of chronic musculoskeletal pain of MPS, and EWST-induced analgesia. Moreover, gaining mechanistic insights into the molecular mechanisms of pain-alleviating effects of ESWT may broaden the fields of shock waves clinical practice far beyond the musculoskeletal system or its original application for lithotripsy.
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Affiliation(s)
- Larisa Ryskalin
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Via Roma 55, 56126 Pisa, Italy
- Center for Rehabilitative Medicine "Sport and Anatomy", University of Pisa, 56121 Pisa, Italy
| | - Gabriele Morucci
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Via Roma 55, 56126 Pisa, Italy
- Center for Rehabilitative Medicine "Sport and Anatomy", University of Pisa, 56121 Pisa, Italy
| | - Gianfranco Natale
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Via Roma 55, 56126 Pisa, Italy
- Center for Rehabilitative Medicine "Sport and Anatomy", University of Pisa, 56121 Pisa, Italy
- Museum of Human Anatomy "Filippo Civinini", University of Pisa, 56126 Pisa, Italy
| | - Paola Soldani
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Via Roma 55, 56126 Pisa, Italy
- Center for Rehabilitative Medicine "Sport and Anatomy", University of Pisa, 56121 Pisa, Italy
| | - Marco Gesi
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Via Roma 55, 56126 Pisa, Italy
- Center for Rehabilitative Medicine "Sport and Anatomy", University of Pisa, 56121 Pisa, Italy
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20
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Wuerfel T, Schmitz C, Jokinen LLJ. The Effects of the Exposure of Musculoskeletal Tissue to Extracorporeal Shock Waves. Biomedicines 2022; 10:biomedicines10051084. [PMID: 35625821 PMCID: PMC9138291 DOI: 10.3390/biomedicines10051084] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Revised: 05/01/2022] [Accepted: 05/04/2022] [Indexed: 12/14/2022] Open
Abstract
Extracorporeal shock wave therapy (ESWT) is a safe and effective treatment option for various pathologies of the musculoskeletal system. Many studies address the molecular and cellular mechanisms of action of ESWT. However, to date, no uniform concept could be established on this matter. In the present study, we perform a systematic review of the effects of exposure of musculoskeletal tissue to extracorporeal shock waves (ESWs) reported in the literature. The key results are as follows: (i) compared to the effects of many other forms of therapy, the clinical benefit of ESWT does not appear to be based on a single mechanism; (ii) different tissues respond to the same mechanical stimulus in different ways; (iii) just because a mechanism of action of ESWT is described in a study does not automatically mean that this mechanism is relevant to the observed clinical effect; (iv) focused ESWs and radial ESWs seem to act in a similar way; and (v) even the most sophisticated research into the effects of exposure of musculoskeletal tissue to ESWs cannot substitute clinical research in order to determine the optimum intensity, treatment frequency and localization of ESWT.
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21
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Sansone V, Ravier D, Pascale V, Applefield R, Del Fabbro M, Martinelli N. Extracorporeal Shockwave Therapy in the Treatment of Nonunion in Long Bones: A Systematic Review and Meta-Analysis. J Clin Med 2022; 11:1977. [PMID: 35407583 PMCID: PMC8999664 DOI: 10.3390/jcm11071977] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Revised: 03/28/2022] [Accepted: 03/29/2022] [Indexed: 02/01/2023] Open
Abstract
Background: Nonunion is one of the most challenging problems in the field of orthopedics. The aim of this study was to perform a systematic review of the literature to evaluate the effectiveness of extracorporeal shockwave therapy (ESWT) in the treatment of nonunion in long bones. Methods: We conducted a search of three databases (PubMed, Scopus, and Web of Science) and found 646 total publications, of which 23 met our inclusion criteria. Results: Out of 1200 total long bone nonunions, 876 (73%) healed after being treated with ESWT. Hypertrophic cases achieved 3-fold higher healing rates when compared to oligotrophic or atrophic cases (p = 0.003). Metatarsal bones were the most receptive to ESWT, achieving a healing rate of 90%, followed by tibiae (75.54%), femurs (66.9%) and humeri (63.9%). Short periods between injury and treatment lead to higher healing rates (p < 0.02). Conversely, 6 months of follow-up after the treatment appears to be too brief to evaluate the full healing potential of the treatment; several studies showed that healing rates continued to increase at follow-ups beyond 6 months after the last ESWT treatment (p < 0.01). Conclusions: ESWT is a promising approach for treating nonunions. At present, a wide range of treatment protocols are used, and more research is needed to determine which protocols are the most effective.
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Affiliation(s)
- Valerio Sansone
- Department of Orthopedics, IRCCS Orthopedic Institute Galeazzi, Via R. Galeazzi 4, 20100 Milan, Italy; (V.S.); (D.R.); (V.P.); (R.A.); (M.D.F.)
- Department of Biomedical, Surgical and Dental Sciences, University of Milan, 20122 Milan, Italy
| | - Domenico Ravier
- Department of Orthopedics, IRCCS Orthopedic Institute Galeazzi, Via R. Galeazzi 4, 20100 Milan, Italy; (V.S.); (D.R.); (V.P.); (R.A.); (M.D.F.)
| | - Valerio Pascale
- Department of Orthopedics, IRCCS Orthopedic Institute Galeazzi, Via R. Galeazzi 4, 20100 Milan, Italy; (V.S.); (D.R.); (V.P.); (R.A.); (M.D.F.)
- Department of Biomedical, Surgical and Dental Sciences, University of Milan, 20122 Milan, Italy
| | - Rachel Applefield
- Department of Orthopedics, IRCCS Orthopedic Institute Galeazzi, Via R. Galeazzi 4, 20100 Milan, Italy; (V.S.); (D.R.); (V.P.); (R.A.); (M.D.F.)
| | - Massimo Del Fabbro
- Department of Orthopedics, IRCCS Orthopedic Institute Galeazzi, Via R. Galeazzi 4, 20100 Milan, Italy; (V.S.); (D.R.); (V.P.); (R.A.); (M.D.F.)
- Department of Biomedical, Surgical and Dental Sciences, University of Milan, 20122 Milan, Italy
| | - Nicolò Martinelli
- Department of Orthopedics, IRCCS Orthopedic Institute Galeazzi, Via R. Galeazzi 4, 20100 Milan, Italy; (V.S.); (D.R.); (V.P.); (R.A.); (M.D.F.)
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22
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Ye F, Li J, Xu P, Xie Z, Zheng G, Liu W, Ye G, Yu W, Lin J, Su Z, Che Y, Zhang Z, Wang P, Wu Y, Shen H. Osteogenic differentiation of mesenchymal stem cells promotes c-Jun-dependent secretion of interleukin 8 and mediates the migration and differentiation of CD4+ T cells. Stem Cell Res Ther 2022; 13:58. [PMID: 35123547 PMCID: PMC8818240 DOI: 10.1186/s13287-022-02735-0] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Accepted: 10/25/2021] [Indexed: 02/07/2023] Open
Abstract
Background The immune system and the skeletal system have complex interactions in the bone marrow and even in the joints, which has promoted the development of the concept of osteoimmunology. Some evidence has indicated that T cells and B cells contribute to the balance between the resorption and formation of bone. However, there has been little discussion on the regulation of CD4+ T lymphocytes by cells involved in bone metabolism. Mesenchymal stem cells (MSCs), which exert core functions related to immunoregulation and osteogenic differentiation, are crucial cells linked to both bone metabolism and the immune system. Previous studies have shown that the immunoregulatory capacity of MSCs changes following differentiation. However, it is still unclear whether the osteogenic differentiation of MSCs affects the migration and differentiation of CD4+ T cells. Methods MSCs were cultured in growth medium or osteogenic medium for 10 days and then cocultured with CD4+ T cells. CD4+ T cell migration and differentiation were detected by flow cytometry. Further, gene expression levels of specific cytokines were analyzed by quantitative real-time PCR and enzyme-linked immunosorbent assays. A Proteome Profiler Human XL Cytokine Array Kit was used to analyze supernatants collected from MSCs. Alizarin red S staining and Alkaline phosphatase assay were used to detect the osteogenic differentiation of MSCs. Results Here, we found that the migration of CD4+ T cells was elevated, and the capacity to induce the differentiation of regulatory T (Treg) cells was weakened during MSC osteogenic differentiation, while the differentiation of T helper 1 (Th1), T helper 2 (Th2) and T helper 17 (Th17) cells was not affected. Further studies revealed that interleukin (IL)-8 was significantly upregulated during MSC osteogenic differentiation. Both a neutralizing antibody and IL-8-specific siRNA significantly inhibited the migration of CD4+ T cells and promoted the differentiation of Treg cells. Finally, we found that the transcription factor c-Jun was involved in regulating the expression of IL-8 and affected the osteogenic differentiation of MSCs, thereby mediating the migration and differentiation of CD4+ T cells. Conclusion This study demonstrated that MSC osteogenic differentiation promoted c-Jun-dependent secretion of IL-8 and mediated the migration and differentiation of CD4+ T cells. These results provide a further understanding of the crosstalk between bone and the immune system and reveal information about the relationship between osteogenesis and inflammation in the field of osteoimmunology. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-022-02735-0.
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Calabrese EJ, Agathokleous E, Dhawan G, Kapoor R, Calabrese V. Human dental pulp stem cells and hormesis. Ageing Res Rev 2022; 73:101540. [PMID: 34890824 DOI: 10.1016/j.arr.2021.101540] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 11/26/2021] [Accepted: 12/05/2021] [Indexed: 02/06/2023]
Abstract
This paper represents the first assessment of hormetic dose responses by human dental pulp stem cells (hDPSCs) with particular emphasis on cell renewal (proliferation) and differentiation. Hormetic dose responses were commonly reported in this model, encompassing a broad range of chemicals, including principally pharmaceuticals (e.g., metformin and artemisinin), dietary supplements/extracts from medicinal plants (e.g., berberine, N-acetyl-L-cysteine, and ginsenoside Rg1) and endogenous agents (e.g., ATP, TNF-α). The paper assesses mechanistic foundations of the hDPSCs hormetic dose responses for both cell proliferation and cell differentiation, study design considerations, and therapeutic implications.
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24
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Gu F, Zhang K, Li J, Xie X, Wen Q, Sui Z, Su Z, Yu T. Changes of Migration, Immunoregulation and Osteogenic Differentiation of Mesenchymal Stem Cells in Different Stages of Inflammation. Int J Med Sci 2022; 19:25-33. [PMID: 34975296 PMCID: PMC8692114 DOI: 10.7150/ijms.58428] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Accepted: 10/25/2021] [Indexed: 12/17/2022] Open
Abstract
Bone infection has always been the focus of orthopedic research. Mesenchymal stem cells (MSCs) are the natural progenitors of osteoblasts, and the process of osteogenesis is triggered in response to different signals from the extracellular matrix. MSCs exert important functions including secretion and immune regulation and also play a key role in bone regeneration. The biological behavior of MSCs in acute and chronic inflammation, especially the transformation between acute inflammation and chronic inflammation, has aroused great interest among researchers. This paper reviews the recent literature and summarizes the behavior and biological characteristics of MSCs in acute and chronic inflammation to stimulate further research on MSCs and treatment of bone diseases.
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Affiliation(s)
- Feng Gu
- Department of Orthopedics, First Hospital of Jilin University, Changchun 130021, Jilin, China
| | - Ke Zhang
- Department of Orthopedics, First Hospital of Jilin University, Changchun 130021, Jilin, China
| | - Jiangbi Li
- Department of Orthopedics, First Hospital of Jilin University, Changchun 130021, Jilin, China
| | - Xiaoping Xie
- Department of Orthopedics, First Hospital of Jilin University, Changchun 130021, Jilin, China
| | - Qiangqiang Wen
- Department of Orthopedics, First Hospital of Jilin University, Changchun 130021, Jilin, China
| | - Zhenjiang Sui
- Department of Orthopedics, First Hospital of Jilin University, Changchun 130021, Jilin, China
| | - Zilong Su
- Department of Orthopedics, First Hospital of Jilin University, Changchun 130021, Jilin, China
| | - Tiecheng Yu
- Department of Orthopedics, First Hospital of Jilin University, Changchun 130021, Jilin, China
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25
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Ramesh S, Zaman F, Sävendahl L, Madhuri V. Radial shockwave treatment promotes chondrogenesis in human growth plate and longitudinal bone growth in rabbits. Bone 2022; 154:116186. [PMID: 34520899 DOI: 10.1016/j.bone.2021.116186] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 09/06/2021] [Accepted: 09/07/2021] [Indexed: 11/17/2022]
Abstract
OBJECTIVE The process of longitudinal bone growth occurs at the growth plate where the chondrocytes undergo apparent structural and molecular changes to promote growth. Recent reports suggest that radial shockwave treatment (rSWT) stimulates bone length in cultured fetal rat metatarsals. Therefore, we investigated if rSWT has similar growth promoting effects on cultured human growth plate fragments and addressed the same in a preclinical in vivo rabbit model by subjecting their growth plates to rSWT. METHODS Short-term effects of high-energy rSWT were evaluated in a unique model of cultured human growth plate cartilage (n = 5) wherein samples exposed to rSWT were assessed for chondrogenic markers at 24 h in comparison to unexposed samples obtained from the same limb. Local in vivo effects were studied in six-week-old rabbits who had their distal femurs exposed to four weekly sessions of rSWT at low- and high-energy levels (n = 4 each). At sacrifice, histomorphometric and immunohistochemistry analyses were performed. For effect on longitudinal growth, proximal tibiae of 22-week-old rabbits (n = 12) were asymmetrically exposed to rSWT; the contralateral side served as untreated controls. At sacrifice, the final bone length was measured. RESULTS In the ex vivo model of cultured human growth plate cartilage, rSWT exposure upregulated SOX9 and COL2A1 compared to control. In the immature rabbit model, an increased number of proliferative chondrocytes and column density was seen for both the energy levels. In the adolescent rabbits, an increase in tibial length was observed after the fourth session of high-energy rSWT and until six-weeks after rSWT compared to the untreated limb. CONCLUSIONS Our preliminary experimental results suggest that rSWT may serve as a non-invasive treatment and possibly a safe strategy to stimulate longitudinal bone growth. However, further studies are needed to assess the in vivo effects of rSWT in models of disturbed bone growth.
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Affiliation(s)
- Sowmya Ramesh
- Department of Paediatric Orthopaedics, Christian Medical College, Vellore, India; Division of Paediatric Endocrinology, Department of Women's and Children's Health, Karolinska Institutet, Solna, Sweden; Centre for Stem Cell Research, a Unit of InStem Bengaluru, Christian Medical College, Bagayam, Vellore, India.
| | - Farasat Zaman
- Division of Paediatric Endocrinology, Department of Women's and Children's Health, Karolinska Institutet, Solna, Sweden.
| | - Lars Sävendahl
- Division of Paediatric Endocrinology, Department of Women's and Children's Health, Karolinska Institutet, Solna, Sweden; Paediatric Endocrinology and Metabolism, Astrid Lindgren Children's Hospital, Karolinska University Hospital, Solna, Sweden.
| | - Vrisha Madhuri
- Department of Paediatric Orthopaedics, Christian Medical College, Vellore, India; Centre for Stem Cell Research, a Unit of InStem Bengaluru, Christian Medical College, Bagayam, Vellore, India.
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26
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Shen PC, Chou SH, Lu CC, Huang HT, Chien SH, Huang PJ, Liu ZM, Shih CL, Su SJ, Chen LM, Tien YC. Shockwave Treatment Enhanced Extracellular Matrix Production in Articular Chondrocytes Through Activation of the ROS/MAPK/Nrf2 Signaling Pathway. Cartilage 2021; 13:238S-253S. [PMID: 34238028 PMCID: PMC8804851 DOI: 10.1177/19476035211012465] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
OBJECTIVE Shockwave application is a potential treatment for osteoarthritis (OA), but the underlying mechanism remains unknown. Oxidative stress and a counterbalancing antioxidant system might be the key to understanding this mechanism. We hypothesized that reactive oxygen species (ROS) and the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2),which is an important regulator of cellular redox homeostasis, are plausible elements. DESIGN Porcine chondrocytes were cultured in a 3-dimensional pellet model and subjected to shockwaves. The effects of shockwaves with various energy-flux densities on optimal extracellular matrix (ECM) synthesis were assessed. ROS, mitogen-activated protein kinase (MAPK) signaling, and the redox activity of Nrf2 were measured. To investigate the signaling mechanism involved in the shockwave treatment in chondrocytes, specific inhibitors of ROS, MAPK signaling, and Nrf2 activity were targeted. RESULTS Shockwaves increased ECM synthesis without affecting cell viability or proliferation. Furthermore, they induced transient ROS production mainly through xanthine oxidase. The phosphorylation of ERK1/2 and p38 and the nuclear translocation of Nrf2 were activated by shockwaves. By contrast, suppression of ROS signaling mitigated shockwave-induced MAPK phosphorylation, Nrf2 nuclear translocation, and ECM synthesis. Pretreatment of chondrocytes with the specific inhibitors of MEK1/2 and p38, respectively, mitigated the shockwave-induced nuclear translocation of Nrf2 and ECM synthesis. Nrf2 inhibition by both small hairpin RNA knockdown and brusatol reduced the shockwave-enhanced ECM synthesis. CONCLUSIONS Shockwaves activated Nrf2 activity through the induction of transient ROS signaling and subsequently enhanced ECM synthesis in chondrocytes. This study provided fundamental evidence confirming the potential of shockwaves for OA management.
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Affiliation(s)
- Po-Chih Shen
- Department of Orthopaedic Surgery,
Kaohsiung Medical University Hospital, Kaohsiung,Graduate Institute of Medicine, College
of Medicine, Kaohsiung Medical University, Kaohsiung
| | - Shih-Hsiang Chou
- Department of Orthopaedic Surgery,
Kaohsiung Medical University Hospital, Kaohsiung
| | - Cheng-Chang Lu
- Department of Orthopaedic Surgery,
Kaohsiung Medical University Hospital, Kaohsiung,Graduate Institute of Medicine, College
of Medicine, Kaohsiung Medical University, Kaohsiung,Department of Orthopaedic Surgery,
Kaohsiung Municipal Siaoqang Hospital, Kaohsiung
| | - Hsuan-Ti Huang
- Department of Orthopaedic Surgery,
Kaohsiung Medical University Hospital, Kaohsiung,Department of Orthopaedic Surgery,
Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung
| | - Song-Hsiung Chien
- Department of Orthopaedic Surgery,
Kaohsiung Medical University Hospital, Kaohsiung
| | - Peng-Ju Huang
- Department of Orthopaedic Surgery,
Kaohsiung Medical University Hospital, Kaohsiung
| | - Zi-Miao Liu
- Department of Orthopaedic Surgery,
Kaohsiung Medical University Hospital, Kaohsiung
| | - Chia-Lung Shih
- Department of Orthopaedic Surgery,
Kaohsiung Medical University Hospital, Kaohsiung
| | - Shu-Jem Su
- Department of Medical Laboratory
Science and Biotechnology, School of Medicine and Health Sciences, Fooyin
University, Kaohsiung
| | - Li-Min Chen
- Departments of Pediatrics, E-DA
Hospital, I-Shou University, Kaohsiung City
| | - Yin-Chun Tien
- Department of Orthopaedic Surgery,
Kaohsiung Medical University Hospital, Kaohsiung,Graduate Institute of Medicine, College
of Medicine, Kaohsiung Medical University, Kaohsiung,Yin-Chun Tien, Department of Orthopaedic
Surgery, Kaohsiung Medical University Hospital, 100 Tzu-You 1st Road, Kaohsiung
807.
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27
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Calabrese EJ. Hormesis and bone marrow stem cells: Enhancing cell proliferation, differentiation and resilience to inflammatory stress. Chem Biol Interact 2021; 351:109730. [PMID: 34728189 DOI: 10.1016/j.cbi.2021.109730] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Revised: 10/13/2021] [Accepted: 10/27/2021] [Indexed: 12/21/2022]
Abstract
This paper identifies and provides the first detailed assessment of hormetic dose responses by bone marrow stem cells (BMSCs) from a broad range of animal models and humans with particular emphasis on cell renewal (proliferation), cell differentiation and enhancing resilience to inflammatory stress. Such hormetic dose responses are commonly reported, being induced by a broad range of chemicals, including pharmaceuticals (e.g., caffeine, dexamethasone, nicotine), dietary supplements (e.g., curcumin, Ginkgo biloba, green tea extracts. resveratrol, sulforaphane), endogenous agents (e.g., hydrogen sulfide, interleukin 10), environmental contaminants (e.g., arsenic, PFOS) and physical stressor agents (e.g., EMF, shockwaves). Hormetic dose responses reported here for BMSCs are similar to those induced with other stem cell types [e.g., adipose-derived stem cells (ADSCs), dental pulp stem cells (DPSCs), periodontal ligament stem cells (PDLSCs), neuro stem cells (NSCs), embryonic stem cells (ESCs)], indicating a substantial degree of generality for hormetic responses in stem cells. The paper assesses both the underlying mechanistic foundations of BMSC hormetic responses and their potential therapeutic implications.
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Affiliation(s)
- Edward J Calabrese
- Professor of Toxicology, Environmental Health Sciences, School of Public Health and Health Sciences, Morrill I, N344, University of Massachusetts, Amherst, MA, 01003, USA.
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28
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Cai X, Yao Y, Teng F, Li Y, Wu L, Yan W, Lin N. The role of P2X7 receptor in infection and metabolism: Based on inflammation and immunity. Int Immunopharmacol 2021; 101:108297. [PMID: 34717202 DOI: 10.1016/j.intimp.2021.108297] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Revised: 10/15/2021] [Accepted: 10/19/2021] [Indexed: 12/20/2022]
Abstract
The P2X7 receptor (P2X7R) is a ligand-gated receptor belonging to the P2 receptor family. It is distributed in various tissues of the human body and is involved in regulating the physiological functions of tissues and cells to affect the occurrence and development of diseases. Unlike all other P2 receptors, the P2X7 receptor is mainly expressed in immune cells and can be activated not only by extracellular nucleotides but also by non-nucleotide substances which act as positive allosteric modulators. In this review, we comprehensively describe the role of the P2X7 receptor in infection and metabolism based on its role as an important regulator of inflammation and immunity, and briefly introduce the structure and general function of the P2X7 receptor. These provide a clear knowledge framework for the study of the P2X7 receptor in human health. Targeting the P2X7 receptor may be an effective method for the treatment of inflammatory and immune diseases. And its role in microbial infection and metabolism may be the main direction for in-depth research on the P2X7 receptor in the future.
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Affiliation(s)
- Xiaoyu Cai
- Department of Clinical Pharmacology, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, Cancer Center, Zhejiang University School of Medicine, Hangzhou 310006, China
| | - Yao Yao
- Department of Pharmacy, Women's Hospital School of Medicine Zhejiang University, Hangzhou 310006, China
| | - Fei Teng
- College of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China
| | - Yangling Li
- Department of Clinical Pharmacology, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, Cancer Center, Zhejiang University School of Medicine, Hangzhou 310006, China
| | - Linwen Wu
- Department of Clinical Pharmacology, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, Cancer Center, Zhejiang University School of Medicine, Hangzhou 310006, China
| | - Wei Yan
- Department of Clinical Pharmacology, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, Cancer Center, Zhejiang University School of Medicine, Hangzhou 310006, China.
| | - Nengming Lin
- Department of Clinical Pharmacology, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, Cancer Center, Zhejiang University School of Medicine, Hangzhou 310006, China; College of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China.
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29
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Lighting up ATP in cells and tissues using a simple aptamer-based fluorescent probe. Mikrochim Acta 2021; 188:352. [PMID: 34554325 PMCID: PMC8459148 DOI: 10.1007/s00604-021-05012-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Accepted: 08/28/2021] [Indexed: 01/02/2023]
Abstract
Extracellular ATP as a purinergic signaling molecule, together with ATP receptor, are playing an important role in tumor growth, therapy resistance, and host immunity suppression. Meanwhile ATP is a crucial indicator for cellular energy status and viability, thus a vital variable for tissue regeneration and in vitro tissue engineering. Most recent studies on COVID-19 virus suggest infection caused ATP deficit and release as a major characterization at the early stage of the disease and major causes for disease complications. Thus, imaging ATP molecule in both cellular and extracellular contexts has many applications in biology, engineering, and clinics. A sensitive and selective fluorescence “signal-on” probe for ATP detection was constructed, based on the base recognition between a black hole quencher (BHQ)-labeled aptamer oligonucleotide and a fluorophore (Cy5)-labeled reporter flare. The probe was able to detect ATP in solution with single digit µM detection limit. With the assistance of lipofectamine, this probe efficiently entered and shined in the model cells U2OS within 3 h. Further application of the probe in specific scenery, cardio-tissue engineering, was also tested where the ATP aptamer complex was able to sense cellular ATP status in a semi-quantitative manner, representing a novel approach for selection of functional cardiomyocytes for tissue engineering. At last a slight change in probe configuration in which a flexible intermolecular A14 linker was introduced granted regeneration capability. These data support the application of this probe in multiple circumstances where ATP measurement or imaging is on demand.
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30
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Dahm F, Feichtinger X, Vallant SM, Haffner N, Schaden W, Fialka C, Mittermayr R. High-energy extracorporeal shockwave therapy in humeral delayed and non-unions. Eur J Trauma Emerg Surg 2021; 48:3043-3049. [PMID: 34515810 DOI: 10.1007/s00068-021-01782-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Accepted: 08/30/2021] [Indexed: 10/20/2022]
Abstract
INTRODUCTION Within the last few decades, focused high-energy extracorporeal shockwave therapy (ESWT) has proven to be an effective alternative to standard of care revision surgery in delayed healing fractures or manifest non-unions in various anatomical regions. MATERIALS AND METHODS A retrospective multi-variant analysis of an open prospective, single-armed clinical study was conducted. Patients receiving focused high-energy ESWT for a delayed healing or an apparent non-union of a humeral fracture between January 1999 and December 2015 at a single trauma center were included in the study. Bony healing was defined as cortical continuity in three of four cortices and pain-free force loading and evaluated using CT scans and clinical examination at three- and six-month follow-ups after ESWT. RESULTS A total of 236 patients were included. N = 93 (43.8%) showed bony consolidation three months after ESWT and n = 105 (52.5%) after six months. Sub-group analysis showed significantly better healing for the proximal metaphyseal humerus (66.7% after six months, n = 42) compared to the diaphyseal region (48.1%, n = 133) and distal metaphyseal humerus (48.1%, n = 25). Regression analysis indicated significantly increased healing rates for patients of younger ages (p = 0.001) and a fracture diastasis of less than 5 mm (p = 0.002). CONCLUSION The findings of this study indicate that ESWT can be considered as a treatment option for a well-selected patient population despite the lower healing rates compared to other anatomical regions.
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Affiliation(s)
- Falko Dahm
- AUVA Trauma Center Meidling, Kundratstr. 37, 1120, Vienna, Austria. .,Women's College Hospital, University of Toronto Orthopaedics Sports Medicine, Toronto, Canada.
| | - Xaver Feichtinger
- AUVA Trauma Center Meidling, Kundratstr. 37, 1120, Vienna, Austria.,Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, Vienna, Austria
| | | | - Nicolas Haffner
- Department for Orthopedics and Trauma Surgery, Krankenhaus Nord-Klinik Floridsdorf, Vienna, Austria
| | - Wolfgang Schaden
- AUVA Trauma Center Meidling, Kundratstr. 37, 1120, Vienna, Austria.,Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, Vienna, Austria.,Austrian Cluster for Tissue Regeneration, Vienna, Austria
| | - Christian Fialka
- AUVA Trauma Center Meidling, Kundratstr. 37, 1120, Vienna, Austria.,Medical Faculty, Sigmund Freud University, Vienna, Austria
| | - Rainer Mittermayr
- AUVA Trauma Center Meidling, Kundratstr. 37, 1120, Vienna, Austria.,Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, Vienna, Austria.,Austrian Cluster for Tissue Regeneration, Vienna, Austria
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Extracorporeal Shockwave Therapy for the Treatment of Tendinopathies: Current Evidence on Effectiveness, Mechanisms, Limitations and Future Directions. CURRENT PHYSICAL MEDICINE AND REHABILITATION REPORTS 2021. [DOI: 10.1007/s40141-021-00324-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
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Schroeder AN, Tenforde AS, Jelsing EJ. Extracorporeal Shockwave Therapy in the Management of Sports Medicine Injuries. Curr Sports Med Rep 2021; 20:298-305. [PMID: 34099607 DOI: 10.1249/jsr.0000000000000851] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
ABSTRACT Treatment of musculoskeletal conditions in athletes with extracorporeal shockwave therapy (ESWT) is gaining popularity as greater evidence supports its use. ESWT protocols (describing energy flux density, number of impulses, type of shockwave (focused or radial), number/frequency/duration of treatment session, area of application, and postprocedural therapy protocols) can be adjusted in the clinical setting. Protocols vary across studies, and optimal protocols for most indications are yet to be determined. ESWT can safely be used to treat various musculoskeletal conditions in athletes, including rotator cuff tendinopathy, lateral elbow epicondlyopathy, greater trochanteric pain syndrome, hamstring tendinopathy, patellar tendinopathy, Achilles tendinopathy, other tendinopathies, plantar fasciopathy, bone stress injuries, and medial tibial stress syndrome. ESWT can be used to treat in-season athletes, as it often requires no/minimal time away from sport and may result in rapid benefits. ESWT should be used in conjunction with physical therapy to facilitate longer-term gains in function and to optimize healing.
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Affiliation(s)
| | - Adam S Tenforde
- Physical Medicine and Rehabilitation, Spaulding Rehabilitation Hospital, Boston, MA
| | - Elena J Jelsing
- Orthopedic Surgery and Physical Medicine and Rehabilitation, Mayo Clinic, Rochester, MN
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Yang H, Cao Z, Wang Y, Wang J, Gao J, Han B, Yu F, Qin Y, Guo Y. Treadmill exercise influences the microRNA profiles in the bone tissues of mice. Exp Ther Med 2021; 22:1035. [PMID: 34373721 PMCID: PMC8343800 DOI: 10.3892/etm.2021.10467] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Accepted: 05/28/2021] [Indexed: 12/12/2022] Open
Abstract
As an important regulator involved in cell activity, microRNAs (miRNAs) are important in the process of exercise influencing bone metabolism. The present study aimed to detect and select differentially expressed miRNAs in the bone tissues of mice trained on a treadmill, predict the target genes of these differentially expressed miRNAs and lay a foundation for exploring the effect of treadmill training on bone metabolism through miRNAs. In this experiment, after the mice were trained on a treadmill for 8 weeks, the mechanical properties of mouse femur bone were assessed, and the alkaline phosphatase (ALP) activity and osteocalcin (OCN) protein levels of the bone were assayed. miRNA microarray and reverse transcription-quantitative (RT-q)PCR were performed to select and validate differentially expressed miRNAs in the bone, and the target genes of these miRNAs were predicted with bioinformatics methods. In addition, the differentially expressed miRNAs in the bone tissues were compared with those in mechanically strained osteocytes in vitro. Treadmill training improved the mechanical properties of the femur bones of mice, and elevated the ALP activity and OCN protein level in the bone. In addition, 122 differentially expressed miRNAs were detected in the bone, of which nine were validated via RT-qPCR. Among the target genes of these differentially expressed miRNAs, certain candidates were involved in bone metabolism. A total of eight miRNAs were differentially expressed in both bone tissue and osteocytes, exhibiting the same expression trends, and various target genes of these eight miRNAs were also involved in bone metabolism. Treadmill training resulted in altered miRNA expression profiles in the bones of mice (mainly in osteocytes) and the differentially expressed miRNAs may serve important roles in regulating bone metabolism and osteogenic differentiation.
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Affiliation(s)
- Huan Yang
- Department of Biomedical Engineering, College of Biotechnology, Guilin Medical University, Guilin, Guangxi 541004, P.R. China
| | - Zhen Cao
- Department of Biomedical Engineering, College of Biotechnology, Guilin Medical University, Guilin, Guangxi 541004, P.R. China
| | - Yang Wang
- Department of Biomedical Engineering, College of Biotechnology, Guilin Medical University, Guilin, Guangxi 541004, P.R. China.,Department of Biomedical Engineering, Bioengineering College of Chongqing University, Chongqing 400044, P.R. China
| | - Jiahui Wang
- Department of Biomedical Engineering, College of Biotechnology, Guilin Medical University, Guilin, Guangxi 541004, P.R. China
| | - Jintao Gao
- Department of Biomedical Engineering, College of Biotechnology, Guilin Medical University, Guilin, Guangxi 541004, P.R. China
| | - Biao Han
- Department of Biomedical Engineering, College of Biotechnology, Guilin Medical University, Guilin, Guangxi 541004, P.R. China
| | - Fangmei Yu
- Department of Biomedical Engineering, College of Biotechnology, Guilin Medical University, Guilin, Guangxi 541004, P.R. China
| | - Yixiong Qin
- Department of Biomedical Engineering, College of Biotechnology, Guilin Medical University, Guilin, Guangxi 541004, P.R. China
| | - Yong Guo
- Department of Biomedical Engineering, College of Biotechnology, Guilin Medical University, Guilin, Guangxi 541004, P.R. China
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Mittermayr R, Haffner N, Feichtinger X, Schaden W. The role of shockwaves in the enhancement of bone repair - from basic principles to clinical application. Injury 2021; 52 Suppl 2:S84-S90. [PMID: 33714550 DOI: 10.1016/j.injury.2021.02.081] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Revised: 02/19/2021] [Accepted: 02/22/2021] [Indexed: 02/02/2023]
Abstract
Extracorporeal shockwave therapy is a treatment modality, originally introduced into the clinic as lithotripsie, which has also been successfully used in the last two decades in the non-invasive treatment of delayed or non-healing fractures. Initially, the mechanism of action was attributed to microfracture-induced repair, but intensive basic research has now shown that the shockwave generates its effect in tissue via mechanotransduction. Numerous signal transduction pathways have already been demonstrated, which in their entirety trigger an endogenous regeneration process via cell proliferation, migration and differentiation. Clinically, these shockwave-conveyed biological signals support healing of acute, delayed and non-union fractures. The attainable outcome is comparable to surgery but avoiding an open approach with associated potential complications. These advantageous properties with a clearly positive cost-benefit ratio make shockwave therapy a first line treatment in delayed and non-union fractures.
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Affiliation(s)
- Rainer Mittermayr
- Ludwig Boltzmann Institute for experimental and clinical traumatology, Vienna, Austria; AUVA Trauma Center Meidling, Vienna, Austria; AUVA trauma research center, Vienna, Austria; Austrian Cluster for Tissue Engineering, Vienna, Austria.
| | - Nicolas Haffner
- Ludwig Boltzmann Institute for experimental and clinical traumatology, Vienna, Austria; Clinic Floridsdorf, Orthopedic and Traumatology Department, Vienna, Austria
| | | | - Wolfgang Schaden
- Ludwig Boltzmann Institute for experimental and clinical traumatology, Vienna, Austria; AUVA trauma research center, Vienna, Austria; Austrian Cluster for Tissue Engineering, Vienna, Austria; AUVA Medical Board, Vienna, Austria
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Dey K, Roca E, Ramorino G, Sartore L. Progress in the mechanical modulation of cell functions in tissue engineering. Biomater Sci 2021; 8:7033-7081. [PMID: 33150878 DOI: 10.1039/d0bm01255f] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
In mammals, mechanics at multiple stages-nucleus to cell to ECM-underlie multiple physiological and pathological functions from its development to reproduction to death. Under this inspiration, substantial research has established the role of multiple aspects of mechanics in regulating fundamental cellular processes, including spreading, migration, growth, proliferation, and differentiation. However, our understanding of how these mechanical mechanisms are orchestrated or tuned at different stages to maintain or restore the healthy environment at the tissue or organ level remains largely a mystery. Over the past few decades, research in the mechanical manipulation of the surrounding environment-known as substrate or matrix or scaffold on which, or within which, cells are seeded-has been exceptionally enriched in the field of tissue engineering and regenerative medicine. To do so, traditional tissue engineering aims at recapitulating key mechanical milestones of native ECM into a substrate for guiding the cell fate and functions towards specific tissue regeneration. Despite tremendous progress, a big puzzle that remains is how the cells compute a host of mechanical cues, such as stiffness (elasticity), viscoelasticity, plasticity, non-linear elasticity, anisotropy, mechanical forces, and mechanical memory, into many biological functions in a cooperative, controlled, and safe manner. High throughput understanding of key cellular decisions as well as associated mechanosensitive downstream signaling pathway(s) for executing these decisions in response to mechanical cues, solo or combined, is essential to address this issue. While many reports have been made towards the progress and understanding of mechanical cues-particularly, substrate bulk stiffness and viscoelasticity-in regulating the cellular responses, a complete picture of mechanical cues is lacking. This review highlights a comprehensive view on the mechanical cues that are linked to modulate many cellular functions and consequent tissue functionality. For a very basic understanding, a brief discussion of the key mechanical players of ECM and the principle of mechanotransduction process is outlined. In addition, this review gathers together the most important data on the stiffness of various cells and ECM components as well as various tissues/organs and proposes an associated link from the mechanical perspective that is not yet reported. Finally, beyond addressing the challenges involved in tuning the interplaying mechanical cues in an independent manner, emerging advances in designing biomaterials for tissue engineering are also explored.
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Affiliation(s)
- Kamol Dey
- Department of Applied Chemistry and Chemical Engineering, Faculty of Science, University of Chittagong, Bangladesh
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Enhancement of Osteogenic Induction by LL37 Modified with a Collagen-Binding Domain In Vitro and In Vivo. Int J Pept Res Ther 2021. [DOI: 10.1007/s10989-021-10216-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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Ma Y, Ran D, Cao Y, Zhao H, Song R, Zou H, Gu J, Yuan Y, Bian J, Zhu J, Liu Z. The effect of P2X7 on cadmium-induced osteoporosis in mice. JOURNAL OF HAZARDOUS MATERIALS 2021; 405:124251. [PMID: 33168313 DOI: 10.1016/j.jhazmat.2020.124251] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/12/2020] [Revised: 09/05/2020] [Accepted: 10/08/2020] [Indexed: 06/11/2023]
Abstract
Cadmium (Cd), an environmental pollutant, induces osteoporosis by directly destroying bone tissue, but its direct damaging effect on bone cells is not fully illustrated. Here, we treated mouse bone marrow stem cells (BMSC) and bone marrow macrophages (BMM) with Cd, and gave BALB/c mice Cd in water. Long-term Cd exposure significantly inhibited BMSC osteogenesis and osteoclast differentiation in vitro, and induced osteoporosis in vivo. Cd exposure also reduced P2X7 expression dramatically. However, P2X7 deletion significantly inhibited osteoblast and osteoclast differentiation; P2X7 overexpression obviously reduced the suppression effect of Cd on osteoblast and osteoclast differentiation. The suppression of P2X7-PI3K-AKT signaling aggravated the effect of Cd. In mice, short-term Cd exposure did not result in osteoporosis, but bone formation was inhibited, RANKL expression was increased, and osteoclasts were significantly increased in vivo. In vitro, short-term Cd exposure not only increased osteoclast numbers, but also promoted osteoclast adhesion function at late-stage osteoclast differentiation. Cd exposure also reduced P2X7 expression in vivo and in vitro. Our results demonstrate that short-term Cd exposure does not affect osteoblast and osteoclast apoptosis in vivo and in vitro, but long-term Cd exposure significantly increases bone tissue apoptosis. Overall, our results describe a novel mechanism for Cd-induced osteoporosis.
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Affiliation(s)
- Yonggang Ma
- College of Veterinary Medicine, Yangzhou University, Yangzhou, 225009 Jiangsu, PR China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, 225009 Jiangsu, PR China; Joint International Research Laboratory of Agriculture and Agri-Product Safety of the Ministry of Education of China, Yangzhou University, Yangzhou, 225009 Jiangsu, PR China
| | - Di Ran
- College of Veterinary Medicine, Yangzhou University, Yangzhou, 225009 Jiangsu, PR China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, 225009 Jiangsu, PR China
| | - Ying Cao
- College of Veterinary Medicine, Yangzhou University, Yangzhou, 225009 Jiangsu, PR China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, 225009 Jiangsu, PR China; Joint International Research Laboratory of Agriculture and Agri-Product Safety of the Ministry of Education of China, Yangzhou University, Yangzhou, 225009 Jiangsu, PR China
| | - Hongyan Zhao
- College of Veterinary Medicine, Yangzhou University, Yangzhou, 225009 Jiangsu, PR China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, 225009 Jiangsu, PR China; Joint International Research Laboratory of Agriculture and Agri-Product Safety of the Ministry of Education of China, Yangzhou University, Yangzhou, 225009 Jiangsu, PR China
| | - Ruilong Song
- College of Veterinary Medicine, Yangzhou University, Yangzhou, 225009 Jiangsu, PR China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, 225009 Jiangsu, PR China; Joint International Research Laboratory of Agriculture and Agri-Product Safety of the Ministry of Education of China, Yangzhou University, Yangzhou, 225009 Jiangsu, PR China
| | - Hui Zou
- College of Veterinary Medicine, Yangzhou University, Yangzhou, 225009 Jiangsu, PR China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, 225009 Jiangsu, PR China; Joint International Research Laboratory of Agriculture and Agri-Product Safety of the Ministry of Education of China, Yangzhou University, Yangzhou, 225009 Jiangsu, PR China
| | - Jianhong Gu
- College of Veterinary Medicine, Yangzhou University, Yangzhou, 225009 Jiangsu, PR China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, 225009 Jiangsu, PR China; Joint International Research Laboratory of Agriculture and Agri-Product Safety of the Ministry of Education of China, Yangzhou University, Yangzhou, 225009 Jiangsu, PR China
| | - Yan Yuan
- College of Veterinary Medicine, Yangzhou University, Yangzhou, 225009 Jiangsu, PR China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, 225009 Jiangsu, PR China; Joint International Research Laboratory of Agriculture and Agri-Product Safety of the Ministry of Education of China, Yangzhou University, Yangzhou, 225009 Jiangsu, PR China
| | - Jianchun Bian
- College of Veterinary Medicine, Yangzhou University, Yangzhou, 225009 Jiangsu, PR China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, 225009 Jiangsu, PR China; Joint International Research Laboratory of Agriculture and Agri-Product Safety of the Ministry of Education of China, Yangzhou University, Yangzhou, 225009 Jiangsu, PR China
| | - Jiaqiao Zhu
- College of Veterinary Medicine, Yangzhou University, Yangzhou, 225009 Jiangsu, PR China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, 225009 Jiangsu, PR China; Joint International Research Laboratory of Agriculture and Agri-Product Safety of the Ministry of Education of China, Yangzhou University, Yangzhou, 225009 Jiangsu, PR China.
| | - Zongping Liu
- College of Veterinary Medicine, Yangzhou University, Yangzhou, 225009 Jiangsu, PR China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, 225009 Jiangsu, PR China; Joint International Research Laboratory of Agriculture and Agri-Product Safety of the Ministry of Education of China, Yangzhou University, Yangzhou, 225009 Jiangsu, PR China.
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Zefferino R, Piccoli C, Di Gioia S, Capitanio N, Conese M. How Cells Communicate with Each Other in the Tumor Microenvironment: Suggestions to Design Novel Therapeutic Strategies in Cancer Disease. Int J Mol Sci 2021; 22:ijms22052550. [PMID: 33806300 PMCID: PMC7961918 DOI: 10.3390/ijms22052550] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Revised: 02/25/2021] [Accepted: 02/26/2021] [Indexed: 02/06/2023] Open
Abstract
Connexin- and pannexin (Panx)-formed hemichannels (HCs) and gap junctions (GJs) operate an interaction with the extracellular matrix and GJ intercellular communication (GJIC), and on account of this they are involved in cancer onset and progression towards invasiveness and metastatization. When we deal with cancer, it is not correct to omit the immune system, as well as neglecting its role in resisting or succumbing to formation and progression of incipient neoplasia until the formation of micrometastasis, nevertheless what really occurs in the tumor microenvironment (TME), which are the main players and which are the tumor or body allies, is still unclear. The goal of this article is to discuss how the pivotal players act, which can enhance or contrast cancer progression during two important process: "Activating Invasion and Metastasis" and the "Avoiding Immune Destruction", with a particular emphasis on the interplay among GJIC, Panx-HCs, and the purinergic system in the TME without disregarding the inflammasome and cytokines thereof derived. In particular, the complex and contrasting roles of Panx1/P2X7R signalosome in tumor facilitation and/or inhibition is discussed in regard to the early/late phases of the carcinogenesis. Finally, considering this complex interplay in the TME between cancer cells, stromal cells, immune cells, and focusing on their means of communication, we should be capable of revealing harmful messages that help the cancer growth and transform them in body allies, thus designing novel therapeutic strategies to fight cancer in a personalized manner.
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Affiliation(s)
- Roberto Zefferino
- Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy; (S.D.G.); (M.C.)
- Correspondence: ; Tel.: +39-0881-884673
| | - Claudia Piccoli
- Department of Clinical and Experimental Medicine, University of Foggia, 71122 Foggia, Italy; (C.P.); (N.C.)
| | - Sante Di Gioia
- Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy; (S.D.G.); (M.C.)
| | - Nazzareno Capitanio
- Department of Clinical and Experimental Medicine, University of Foggia, 71122 Foggia, Italy; (C.P.); (N.C.)
| | - Massimo Conese
- Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy; (S.D.G.); (M.C.)
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Gstoettner C, Salminger S, Sturma A, Moser V, Hausner T, Brånemark R, Aszmann OC. Successful salvage via re-osseointegration of a loosened implant in a patient with transtibial amputation. Prosthet Orthot Int 2021; 45:76-80. [PMID: 33834747 DOI: 10.1177/0309364620953985] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
CASE DESCRIPTION Osseointegration is a relatively new technique for prosthetic limb attachment that offers various improvements for patients with amputation and facilitates joint preservation. We present a case of implant loosening during rehabilitation in a patient with transtibial amputation that was successfully managed through a combination of measures, aiming to promote re-osseointegration of the implant. OBJECTIVES Not much is known about structured management of adverse events after osseointegration. Septic or aseptic loosening is currently regarded as implant failure, prompting removal and possible re-implantation at a later stage. The objective of this case report was to evaluate the feasibility of salvaging a loosened implant. STUDY DESIGN Case report. TREATMENT A novel treatment approach was employed to enable renewed osseointegration of the implant. First, the bone-implant interface was disrupted and renewed through axial rotation and distal repositioning of the implant. Afterwards, extracorporal shockwave therapy and antibiotic treatment were administered. Prosthetic rehabilitation was then started anew. Regular follow-up x-rays and clinical evaluations were conducted, including standardized outcome tests. OUTCOMES These combined measures led to a successful re-osseointegration of the implant. In a 21-month follow-up, the patient regained a stable and secure gait pattern, using his prosthesis every day for 15 hours and scoring above average on standardized outcome measures. CONCLUSION This represents the first report of implant salvage after failed primary osseointegration. As the associated risks of this novel treatment are very low, investigations are warranted to evaluate this approach on a larger scale.
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Affiliation(s)
- Clemens Gstoettner
- Clinical Laboratory for Bionic Extremity Reconstruction, Department of Surgery, Medical University of Vienna, Vienna, Austria
| | - Stefan Salminger
- Clinical Laboratory for Bionic Extremity Reconstruction, Department of Surgery, Medical University of Vienna, Vienna, Austria
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Medical University of Vienna, Vienna, Austria
| | - Agnes Sturma
- Clinical Laboratory for Bionic Extremity Reconstruction, Department of Surgery, Medical University of Vienna, Vienna, Austria
- Department of Bioengineering, Imperial College London, London, UK
| | - Veith Moser
- AUVA Trauma Hospital Lorenz Böhler-European Hand Trauma Center, Vienna, Austria
| | - Thomas Hausner
- AUVA Trauma Hospital Lorenz Böhler-European Hand Trauma Center, Vienna, Austria
- Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, AUVA Research Center, Vienna, Austria
| | - Rickard Brånemark
- Sahlgrenska Academy, Gothenburg University, Gothenburg, Sweden
- Biomechatronics Group, Center for Extreme Bionics, MIT Media Lab, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Oskar C Aszmann
- Clinical Laboratory for Bionic Extremity Reconstruction, Department of Surgery, Medical University of Vienna, Vienna, Austria
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Medical University of Vienna, Vienna, Austria
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Ma Y, Ran D, Zhao H, Song R, Zou H, Gu J, Yuan Y, Bian J, Zhu J, Liu Z. Cadmium exposure triggers osteoporosis in duck via P2X7/PI3K/AKT-mediated osteoblast and osteoclast differentiation. THE SCIENCE OF THE TOTAL ENVIRONMENT 2021; 750:141638. [PMID: 32858297 DOI: 10.1016/j.scitotenv.2020.141638] [Citation(s) in RCA: 69] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Revised: 08/08/2020] [Accepted: 08/09/2020] [Indexed: 06/11/2023]
Abstract
Cadmium is a common environmental pollutant that accumulates in the bone and kidneys and causes severe health and social problems. However, the effects of Cd on the occurrence of osteoporosis and its mechanism of action in this process are unclear. To test whether Cd-induced osteoporosis is mediated via P2X7/PI3K/AKT signaling, duck bone marrow mesenchymal stem cells (BMSCs) and bone marrow macrophage cells (BMMs) were treated with Cd for 5 days, and duck embryos were treated with Cd. Micro-CT analysis indicated that Cd-induced osteoporosis occurs in vivo, and histopathology and immunohistochemical analyses also revealed that Cd induced bone damage and the downregulation of osteogenic and bone resorption-related proteins. Cd exposure significantly inhibited the differentiation of BMSCs and BMMs into osteoblasts and osteoclasts in vitro, and promoted osteoblast and osteoclast apoptosis. Cd exposure significantly downregulated the P2X7/PI3K/AKT signaling pathway in vivo and in vitro, and inhibition of this signaling pathway significantly aggravated osteoblast and osteoclast differentiation. Cd exposure also upregulated the OPG/RANKL ratio in vivo and in vitro, further inhibiting osteoclast differentiation. These results demonstrate that Cd causes osteoporosis in duck by inhibiting P2X7/PI3K/AKT signaling and increasing the OPG/RANKL ratio. These results establish a previously unknown mechanism of Cd-induced osteoporosis.
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Affiliation(s)
- Yonggang Ma
- College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu 225009, PR China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, Jiangsu 225009, PR China; Joint International Research Laboratory of Agriculture and Agri-Product Safety of the Ministry of Education of China, Yangzhou University, Yangzhou, Jiangsu 225009, PR China
| | - Di Ran
- College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu 225009, PR China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, Jiangsu 225009, PR China; Joint International Research Laboratory of Agriculture and Agri-Product Safety of the Ministry of Education of China, Yangzhou University, Yangzhou, Jiangsu 225009, PR China
| | - Hongyan Zhao
- College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu 225009, PR China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, Jiangsu 225009, PR China; Joint International Research Laboratory of Agriculture and Agri-Product Safety of the Ministry of Education of China, Yangzhou University, Yangzhou, Jiangsu 225009, PR China
| | - Ruilong Song
- College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu 225009, PR China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, Jiangsu 225009, PR China; Joint International Research Laboratory of Agriculture and Agri-Product Safety of the Ministry of Education of China, Yangzhou University, Yangzhou, Jiangsu 225009, PR China
| | - Hui Zou
- College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu 225009, PR China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, Jiangsu 225009, PR China; Joint International Research Laboratory of Agriculture and Agri-Product Safety of the Ministry of Education of China, Yangzhou University, Yangzhou, Jiangsu 225009, PR China
| | - Jianhong Gu
- College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu 225009, PR China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, Jiangsu 225009, PR China; Joint International Research Laboratory of Agriculture and Agri-Product Safety of the Ministry of Education of China, Yangzhou University, Yangzhou, Jiangsu 225009, PR China
| | - Yan Yuan
- College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu 225009, PR China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, Jiangsu 225009, PR China; Joint International Research Laboratory of Agriculture and Agri-Product Safety of the Ministry of Education of China, Yangzhou University, Yangzhou, Jiangsu 225009, PR China
| | - Jianchun Bian
- College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu 225009, PR China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, Jiangsu 225009, PR China; Joint International Research Laboratory of Agriculture and Agri-Product Safety of the Ministry of Education of China, Yangzhou University, Yangzhou, Jiangsu 225009, PR China
| | - Jiaqiao Zhu
- College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu 225009, PR China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, Jiangsu 225009, PR China; Joint International Research Laboratory of Agriculture and Agri-Product Safety of the Ministry of Education of China, Yangzhou University, Yangzhou, Jiangsu 225009, PR China.
| | - Zongping Liu
- College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu 225009, PR China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, Jiangsu 225009, PR China; Joint International Research Laboratory of Agriculture and Agri-Product Safety of the Ministry of Education of China, Yangzhou University, Yangzhou, Jiangsu 225009, PR China.
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Zhang Y, Gao H, Li H, Guo J, Ouyang B, Wang M, Xu Q, Wang J, Lv M, Guo X, Liu Q, Wei L, Ren H, Xi Y, Guo Y, Ren B, Pan S, Liu C, Ding X, Xiang H, Yu Y, Song Y, Meng L, Liu S, Wang J, Jiang Y, Shi J, Liu S, Sabir JS, Sabir MJ, Khan M, Hajrah NH, Ming-Yuen Lee S, Xu X, Yang H, Wang J, Fan G, Yang N, Liu X. The White-Spotted Bamboo Shark Genome Reveals Chromosome Rearrangements and Fast-Evolving Immune Genes of Cartilaginous Fish. iScience 2020; 23:101754. [PMID: 33251490 PMCID: PMC7677710 DOI: 10.1016/j.isci.2020.101754] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2020] [Revised: 09/17/2020] [Accepted: 10/28/2020] [Indexed: 01/27/2023] Open
Abstract
Chondrichthyan (cartilaginous fish) occupies a key phylogenetic position and is important for investigating evolutionary processes of vertebrates. However, limited whole genomes impede our in-depth knowledge of important issues such as chromosome evolution and immunity. Here, we report the chromosome-level genome of white-spotted bamboo shark. Combing it with other shark genomes, we reconstructed 16 ancestral chromosomes of bamboo shark and illustrate a dynamic chromosome rearrangement process. We found that genes on 13 fast-evolving chromosomes can be enriched in immune-related pathways. And two chromosomes contain important genes that can be used to develop single-chain antibodies, which were shown to have high affinity to human disease markers by using enzyme-linked immunosorbent assay. We also found three bone formation-related genes were lost due to chromosome rearrangements. Our study highlights the importance of chromosome rearrangements, providing resources for understanding of cartilaginous fish diversification and potential application of single-chain antibodies.
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Affiliation(s)
- Yaolei Zhang
- BGI-Qingdao, BGI-Shenzhen, Qingdao 266555, China
- China National GeneBank, BGI-Shenzhen, Shenzhen 518120, China
- Department of Biotechnology and Biomedicine, Technical University of Denmark, 2800 Lyngby, Denmark
| | - Haoyang Gao
- BGI-Qingdao, BGI-Shenzhen, Qingdao 266555, China
- China National GeneBank, BGI-Shenzhen, Shenzhen 518120, China
| | - Hanbo Li
- BGI-Qingdao, BGI-Shenzhen, Qingdao 266555, China
- China National GeneBank, BGI-Shenzhen, Shenzhen 518120, China
| | - Jiao Guo
- BGI-Qingdao, BGI-Shenzhen, Qingdao 266555, China
- China National GeneBank, BGI-Shenzhen, Shenzhen 518120, China
| | - Bingjie Ouyang
- BGI-Qingdao, BGI-Shenzhen, Qingdao 266555, China
- China National GeneBank, BGI-Shenzhen, Shenzhen 518120, China
| | - Meiniang Wang
- BGI-Shenzhen, Shenzhen 518083, China
- China National GeneBank, BGI-Shenzhen, Shenzhen 518120, China
| | - Qiwu Xu
- BGI-Qingdao, BGI-Shenzhen, Qingdao 266555, China
- China National GeneBank, BGI-Shenzhen, Shenzhen 518120, China
| | - Jiahao Wang
- BGI-Qingdao, BGI-Shenzhen, Qingdao 266555, China
- China National GeneBank, BGI-Shenzhen, Shenzhen 518120, China
| | - Meiqi Lv
- BGI-Qingdao, BGI-Shenzhen, Qingdao 266555, China
- China National GeneBank, BGI-Shenzhen, Shenzhen 518120, China
| | - Xinyu Guo
- BGI-Qingdao, BGI-Shenzhen, Qingdao 266555, China
- China National GeneBank, BGI-Shenzhen, Shenzhen 518120, China
| | - Qun Liu
- BGI-Qingdao, BGI-Shenzhen, Qingdao 266555, China
- China National GeneBank, BGI-Shenzhen, Shenzhen 518120, China
| | - Likun Wei
- City University of Hongkong, Kowloon, Hongkong SAR
| | - Han Ren
- BGI-Shenzhen, Shenzhen 518083, China
- China National GeneBank, BGI-Shenzhen, Shenzhen 518120, China
| | - Yang Xi
- BGI-Shenzhen, Shenzhen 518083, China
- China National GeneBank, BGI-Shenzhen, Shenzhen 518120, China
| | - Yang Guo
- BGI-Qingdao, BGI-Shenzhen, Qingdao 266555, China
- China National GeneBank, BGI-Shenzhen, Shenzhen 518120, China
| | - Bingzhao Ren
- BGI-Qingdao, BGI-Shenzhen, Qingdao 266555, China
- China National GeneBank, BGI-Shenzhen, Shenzhen 518120, China
| | - Shanshan Pan
- BGI-Qingdao, BGI-Shenzhen, Qingdao 266555, China
- China National GeneBank, BGI-Shenzhen, Shenzhen 518120, China
| | - Chuxin Liu
- BGI-Shenzhen, Shenzhen 518083, China
- China National GeneBank, BGI-Shenzhen, Shenzhen 518120, China
| | - Xiaoyan Ding
- BGI-Qingdao, BGI-Shenzhen, Qingdao 266555, China
- China National GeneBank, BGI-Shenzhen, Shenzhen 518120, China
| | - Haitao Xiang
- BGI-Shenzhen, Shenzhen 518083, China
- China National GeneBank, BGI-Shenzhen, Shenzhen 518120, China
| | - Yingjia Yu
- BGI-Qingdao, BGI-Shenzhen, Qingdao 266555, China
- China National GeneBank, BGI-Shenzhen, Shenzhen 518120, China
| | - Yue Song
- BGI-Qingdao, BGI-Shenzhen, Qingdao 266555, China
- China National GeneBank, BGI-Shenzhen, Shenzhen 518120, China
| | - Lingfeng Meng
- BGI-Qingdao, BGI-Shenzhen, Qingdao 266555, China
- China National GeneBank, BGI-Shenzhen, Shenzhen 518120, China
| | - Shanshan Liu
- BGI-Qingdao, BGI-Shenzhen, Qingdao 266555, China
- China National GeneBank, BGI-Shenzhen, Shenzhen 518120, China
| | - Jun Wang
- BGI-Qingdao, BGI-Shenzhen, Qingdao 266555, China
- China National GeneBank, BGI-Shenzhen, Shenzhen 518120, China
| | - Yuan Jiang
- BGI-Shenzhen, Shenzhen 518083, China
- Complete Genomics, Inc., San Jose, CA 95134, USA
| | - Jiahai Shi
- City University of Hongkong, Kowloon, Hongkong SAR
| | - Shiping Liu
- BGI-Shenzhen, Shenzhen 518083, China
- China National GeneBank, BGI-Shenzhen, Shenzhen 518120, China
| | - Jamal S.M. Sabir
- Department of Biological Sciences, King Abdulaziz University (KAU), Jeddah 21589, Saudi Arabia
| | - Mumdooh J. Sabir
- Department of Biological Sciences, King Abdulaziz University (KAU), Jeddah 21589, Saudi Arabia
| | - Muhummadh Khan
- Department of Biological Sciences, King Abdulaziz University (KAU), Jeddah 21589, Saudi Arabia
| | - Nahid H. Hajrah
- Department of Biological Sciences, King Abdulaziz University (KAU), Jeddah 21589, Saudi Arabia
| | - Simon Ming-Yuen Lee
- State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, Macao, China
| | - Xun Xu
- BGI-Shenzhen, Shenzhen 518083, China
- China National GeneBank, BGI-Shenzhen, Shenzhen 518120, China
| | - Huanming Yang
- BGI-Shenzhen, Shenzhen 518083, China
- James D. Watson Institute of Genome Sciences, Hangzhou 310058, China
| | - Jian Wang
- BGI-Shenzhen, Shenzhen 518083, China
- James D. Watson Institute of Genome Sciences, Hangzhou 310058, China
| | - Guangyi Fan
- BGI-Qingdao, BGI-Shenzhen, Qingdao 266555, China
- State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, Macao, China
- China National GeneBank, BGI-Shenzhen, Shenzhen 518120, China
| | - Naibo Yang
- BGI-Shenzhen, Shenzhen 518083, China
- Complete Genomics, Inc., San Jose, CA 95134, USA
| | - Xin Liu
- BGI-Qingdao, BGI-Shenzhen, Qingdao 266555, China
- BGI-Shenzhen, Shenzhen 518083, China
- China National GeneBank, BGI-Shenzhen, Shenzhen 518120, China
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Extracellular Nucleotides Regulate Arterial Calcification by Activating Both Independent and Dependent Purinergic Receptor Signaling Pathways. Int J Mol Sci 2020; 21:ijms21207636. [PMID: 33076470 PMCID: PMC7589647 DOI: 10.3390/ijms21207636] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Revised: 10/09/2020] [Accepted: 10/12/2020] [Indexed: 01/02/2023] Open
Abstract
Arterial calcification, the deposition of calcium-phosphate crystals in the extracellular matrix, resembles physiological bone mineralization. It is well-known that extracellular nucleotides regulate bone homeostasis raising an emerging interest in the role of these molecules on arterial calcification. The purinergic independent pathway involves the enzymes ecto-nucleotide pyrophosphatase/phosphodiesterases (NPPs), ecto-nucleoside triphosphate diphosphohydrolases (NTPDases), 5′-nucleotidase and alkaline phosphatase. These regulate the production and breakdown of the calcification inhibitor—pyrophosphate and the calcification stimulator—inorganic phosphate, from extracellular nucleotides. Maintaining ecto-nucleotidase activities in a well-defined range is indispensable as enzymatic hyper- and hypo-expression has been linked to arterial calcification. The purinergic signaling dependent pathway focusses on the activation of purinergic receptors (P1, P2X and P2Y) by extracellular nucleotides. These receptors influence arterial calcification by interfering with the key molecular mechanisms underlying this pathology, including the osteogenic switch and apoptosis of vascular cells and possibly, by favoring the phenotypic switch of vascular cells towards an adipogenic phenotype, a recent, novel hypothesis explaining the systemic prevention of arterial calcification. Selective compounds influencing the activity of ecto-nucleotidases and purinergic receptors, have recently been developed to treat arterial calcification. However, adverse side-effects on bone mineralization are possible as these compounds reasonably could interfere with physiological bone mineralization.
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Carluccio M, Ziberi S, Zuccarini M, Giuliani P, Caciagli F, Di Iorio P, Ciccarelli R. Adult mesenchymal stem cells: is there a role for purine receptors in their osteogenic differentiation? Purinergic Signal 2020; 16:263-287. [PMID: 32500422 DOI: 10.1007/s11302-020-09703-4] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2019] [Accepted: 05/04/2020] [Indexed: 02/06/2023] Open
Abstract
The role played by mesenchymal stem cells (MSCs) in contributing to adult tissue homeostasis and damage repair thanks to their differentiation capabilities has raised a great interest, mainly in bone regenerative medicine. The growth/function of these undifferentiated cells of mesodermal origin, located in specialized structures (niches) of differentiated organs is influenced by substances present in this microenvironment. Among them, ancestral and ubiquitous molecules such as adenine-based purines, i.e., ATP and adenosine, may be included. Notably, extracellular purine concentrations greatly increase during tissue injury; thus, MSCs are exposed to effects mediated by these agents interacting with their own receptors when they act/migrate in vivo or are transplanted into a damaged tissue. Here, we reported that ATP modulates MSC osteogenic differentiation via different P2Y and P2X receptors, but data are often inconclusive/contradictory so that the ATP receptor importance for MSC physiology/differentiation into osteoblasts is yet undetermined. An exception is represented by P2X7 receptors, whose expression was shown at various differentiation stages of bone cells resulting essential for differentiation/survival of both osteoclasts and osteoblasts. As well, adenosine, usually derived from extracellular ATP metabolism, can promote osteogenesis, likely via A2B receptors, even though findings from human MSCs should be implemented and confirmed in preclinical models. Therefore, although many data have revealed possible effects caused by extracellular purines in bone healing/remodeling, further studies, hopefully performed in in vivo models, are necessary to identify defined roles for these compounds in favoring/increasing the pro-osteogenic properties of MSCs and thereby their usefulness in bone regenerative medicine.
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Affiliation(s)
- Marzia Carluccio
- Department of Medical, Oral and Biotechnological Sciences, University of Chieti-Pescara, Via dei Vestini 29, 66100, Chieti, Italy.,Center for Advanced Studies and Technologies (CAST), University of Chieti-Pescara, Via L. Polacchi, 66100, Chieti, Italy.,StemTeCh Group, Via L. Polacchi, 66100, Chieti, Italy
| | - Sihana Ziberi
- Department of Medical, Oral and Biotechnological Sciences, University of Chieti-Pescara, Via dei Vestini 29, 66100, Chieti, Italy.,Center for Advanced Studies and Technologies (CAST), University of Chieti-Pescara, Via L. Polacchi, 66100, Chieti, Italy.,StemTeCh Group, Via L. Polacchi, 66100, Chieti, Italy
| | - Mariachiara Zuccarini
- Department of Medical, Oral and Biotechnological Sciences, University of Chieti-Pescara, Via dei Vestini 29, 66100, Chieti, Italy.,Center for Advanced Studies and Technologies (CAST), University of Chieti-Pescara, Via L. Polacchi, 66100, Chieti, Italy
| | - Patricia Giuliani
- Department of Medical, Oral and Biotechnological Sciences, University of Chieti-Pescara, Via dei Vestini 29, 66100, Chieti, Italy.,Center for Advanced Studies and Technologies (CAST), University of Chieti-Pescara, Via L. Polacchi, 66100, Chieti, Italy
| | - Francesco Caciagli
- Center for Advanced Studies and Technologies (CAST), University of Chieti-Pescara, Via L. Polacchi, 66100, Chieti, Italy
| | - Patrizia Di Iorio
- Department of Medical, Oral and Biotechnological Sciences, University of Chieti-Pescara, Via dei Vestini 29, 66100, Chieti, Italy.,Center for Advanced Studies and Technologies (CAST), University of Chieti-Pescara, Via L. Polacchi, 66100, Chieti, Italy
| | - Renata Ciccarelli
- Department of Medical, Oral and Biotechnological Sciences, University of Chieti-Pescara, Via dei Vestini 29, 66100, Chieti, Italy. .,Center for Advanced Studies and Technologies (CAST), University of Chieti-Pescara, Via L. Polacchi, 66100, Chieti, Italy. .,StemTeCh Group, Via L. Polacchi, 66100, Chieti, Italy.
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Stokes L, Bidula S, Bibič L, Allum E. To Inhibit or Enhance? Is There a Benefit to Positive Allosteric Modulation of P2X Receptors? Front Pharmacol 2020; 11:627. [PMID: 32477120 PMCID: PMC7235284 DOI: 10.3389/fphar.2020.00627] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Accepted: 04/21/2020] [Indexed: 12/15/2022] Open
Abstract
The family of ligand-gated ion channels known as P2X receptors were discovered several decades ago. Since the cloning of the seven P2X receptors (P2X1-P2X7), a huge research effort has elucidated their roles in regulating a range of physiological and pathophysiological processes. Transgenic animals have been influential in understanding which P2X receptors could be new therapeutic targets for disease. Furthermore, understanding how inherited mutations can increase susceptibility to disorders and diseases has advanced this knowledge base. There has been an emphasis on the discovery and development of pharmacological tools to help dissect the individual roles of P2X receptors and the pharmaceutical industry has been involved in pushing forward clinical development of several lead compounds. During the discovery phase, a number of positive allosteric modulators have been described for P2X receptors and these have been useful in assigning physiological roles to receptors. This review will consider the major physiological roles of P2X1-P2X7 and discuss whether enhancement of P2X receptor activity would offer any therapeutic benefit. We will review what is known about identified compounds acting as positive allosteric modulators and the recent identification of drug binding pockets for such modulators.
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Affiliation(s)
- Leanne Stokes
- School of Pharmacy, University of East Anglia, Norwich, United Kingdom
| | - Stefan Bidula
- School of Pharmacy, University of East Anglia, Norwich, United Kingdom
| | - Lučka Bibič
- School of Pharmacy, University of East Anglia, Norwich, United Kingdom
| | - Elizabeth Allum
- School of Pharmacy, University of East Anglia, Norwich, United Kingdom
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Liu H, Du Y, St-Pierre JP, Bergholt MS, Autefage H, Wang J, Cai M, Yang G, Stevens MM, Zhang S. Bioenergetic-active materials enhance tissue regeneration by modulating cellular metabolic state. SCIENCE ADVANCES 2020; 6:eaay7608. [PMID: 32232154 PMCID: PMC7096169 DOI: 10.1126/sciadv.aay7608] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/22/2019] [Accepted: 01/03/2020] [Indexed: 05/02/2023]
Abstract
Cellular bioenergetics (CBE) plays a critical role in tissue regeneration. Physiologically, an enhanced metabolic state facilitates anabolic biosynthesis and mitosis to accelerate regeneration. However, the development of approaches to reprogram CBE, toward the treatment of substantial tissue injuries, has been limited thus far. Here, we show that induced repair in a rabbit model of weight-bearing bone defects is greatly enhanced using a bioenergetic-active material (BAM) scaffold compared to commercialized poly(lactic acid) and calcium phosphate ceramic scaffolds. This material was composed of energy-active units that can be released in a sustained degradation-mediated fashion once implanted. By establishing an intramitochondrial metabolic bypass, the internalized energy-active units significantly elevate mitochondrial membrane potential (ΔΨm) to supply increased bioenergetic levels and accelerate bone formation. The ready-to-use material developed here represents a highly efficient and easy-to-implement therapeutic approach toward tissue regeneration, with promise for bench-to-bedside translation.
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Affiliation(s)
- Haoming Liu
- Department of Biomedical Engineering, Huazhong University of Science and Technology, Wuhan 430074, China
- Advanced Biomaterials and Tissue Engineering Centre, Huazhong University of Science and Technology, Wuhan 430074, China
| | - Yingying Du
- Department of Biomedical Engineering, Huazhong University of Science and Technology, Wuhan 430074, China
- Advanced Biomaterials and Tissue Engineering Centre, Huazhong University of Science and Technology, Wuhan 430074, China
| | - Jean-Philippe St-Pierre
- Department of Materials, Imperial College London, London SW7 2AZ, UK
- Institute of Biomedical Engineering, Imperial College London, London SW7 2AZ, UK
- Department of Bioengineering, Imperial College London, London SW7 2AZ, UK
| | - Mads S. Bergholt
- Department of Materials, Imperial College London, London SW7 2AZ, UK
- Institute of Biomedical Engineering, Imperial College London, London SW7 2AZ, UK
- Department of Bioengineering, Imperial College London, London SW7 2AZ, UK
| | - Hélène Autefage
- Department of Materials, Imperial College London, London SW7 2AZ, UK
- Institute of Biomedical Engineering, Imperial College London, London SW7 2AZ, UK
- Department of Bioengineering, Imperial College London, London SW7 2AZ, UK
- Division of Biomaterials, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
| | - Jianglin Wang
- Department of Biomedical Engineering, Huazhong University of Science and Technology, Wuhan 430074, China
- Advanced Biomaterials and Tissue Engineering Centre, Huazhong University of Science and Technology, Wuhan 430074, China
| | - Mingle Cai
- Department of Biomedical Engineering, Huazhong University of Science and Technology, Wuhan 430074, China
- Advanced Biomaterials and Tissue Engineering Centre, Huazhong University of Science and Technology, Wuhan 430074, China
| | - Gaojie Yang
- Department of Biomedical Engineering, Huazhong University of Science and Technology, Wuhan 430074, China
- Advanced Biomaterials and Tissue Engineering Centre, Huazhong University of Science and Technology, Wuhan 430074, China
| | - Molly M. Stevens
- Department of Materials, Imperial College London, London SW7 2AZ, UK
- Institute of Biomedical Engineering, Imperial College London, London SW7 2AZ, UK
- Department of Bioengineering, Imperial College London, London SW7 2AZ, UK
- Corresponding author. (M.M.S.); (S.Z.)
| | - Shengmin Zhang
- Department of Biomedical Engineering, Huazhong University of Science and Technology, Wuhan 430074, China
- Advanced Biomaterials and Tissue Engineering Centre, Huazhong University of Science and Technology, Wuhan 430074, China
- Corresponding author. (M.M.S.); (S.Z.)
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Ramesh S, Zaman F, Madhuri V, Sävendahl L. Radial Extracorporeal Shock Wave Treatment Promotes Bone Growth and Chondrogenesis in Cultured Fetal Rat Metatarsal Bones. Clin Orthop Relat Res 2020; 478:668-678. [PMID: 31794485 PMCID: PMC7145076 DOI: 10.1097/corr.0000000000001056] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2019] [Accepted: 11/04/2019] [Indexed: 01/31/2023]
Abstract
BACKGROUND Substantial evidence exists to show the positive effects of radialextracorporeal shock wave therapy (ESWT) on bone formation. However, it is unknown whether rESWT can act locally at the growth plate level to stimulate linear bone growth. One way to achieve this is to stimulate chondrogenesis in the growth plate without depending on circulating systemic growth factors. We wished to see whether rESWT would stimulate metatarsal rat growth plates in the absence of vascularity and associated systemic growth factors. QUESTIONS/PURPOSES To study the direct effects of rESWT on growth plate chondrogenesis, we asked: (1) Does rESWT stimulate longitudinal bone growth of ex vivo cultured bones? (2) Does rESWT cause any morphological changes in the growth plate? (3) Does rESWT locally activate proteins specific to growth plate chondrogenesis? METHODS Metatarsal bones from rat fetuses were untreated (controls: n = 15) or exposed to a single application of rESWT at a low dose (500 impulses, 5 Hz, 90 mJ; n = 15), mid-dose (500 impulses, 5 Hz, 120 mJ; n = 14) or high dose (500 impulses, 10 Hz, 180 mJ; n = 34) and cultured for 14 days. Bone lengths were measured on Days 0, 4, 7, and 14. After 14 days of culturing, growth plate morphology was assessed with a histomorphometric analysis in which hypertrophic cell size (> 7 µm) and hypertrophic zone height were measured (n = 6 bones each). Immunostaining for specific regulatory proteins involved in chondrogenesis and corresponding staining were quantitated digitally by a single observer using the automated threshold method in ImageJ software (n = 6 bones per group). A p value < 0.05 indicated a significant difference. RESULTS The bone length in the high-dose rESWT group was increased compared with that in untreated controls (4.46 mm ± 0.75 mm; 95% confidence interval, 3.28-3.71 and control: 3.50 mm ± 0.38 mm; 95% CI, 4.19-4.72; p = 0.01). Mechanistic studies of the growth plate's cartilage revealed that high-dose rESWT increased the number of proliferative chondrocytes compared with untreated control bones (1363 ± 393 immunopositive cells per bone and 500 ± 413 immunopositive cells per bone, respectively; p = 0.04) and increased the diameter of hypertrophic chondrocytes (18 ± 3 µm and 13 ± 3 µm, respectively; p < 0.001). This was accompanied by activation of insulin-like growth factor-1 (1015 ± 322 immunopositive cells per bone and 270 ± 121 immunopositive cells per bone, respectively; p = 0.043) and nuclear factor-kappa beta signaling (1029 ± 262 immunopositive cells per bone and 350 ± 60 immunopositive cells per bone, respectively; p = 0.01) and increased levels of the anti-apoptotic proteins B-cell lymphoma 2 (718 ± 86 immunopositive cells per bone and 35 ± 11 immunopositive cells per bone, respectively; p < 0.001) and B-cell lymphoma-extra-large (107 ± 7 immunopositive cells per bone and 34 ± 6 immunopositive cells per bone, respectively; p < 0.001). CONCLUSION In a model of cultured fetal rat metatarsals, rESWT increased longitudinal bone growth by locally inducing chondrogenesis. To verify whether rESWT can also stimulate bone growth in the presence of systemic circulatory factors, further studies are needed. CLINICAL RELEVANCE This preclinical proof-of-concept study shows that high-dose rESWT can stimulate longitudinal bone growth and growth plate chondrogenesis in cultured fetal rat metatarsal bones. A confirmatory in vivo study in skeletally immature animals must be performed before any clinical studies.
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Affiliation(s)
- Sowmya Ramesh
- S. Ramesh, V. Madhuri, Paediatric Orthopaedics, Christian Medical College and Hospital, Vellore, India
- S. Ramesh, F. Zaman, L. Sävendahl, Department of Women's and Children's Health and Paediatric Endocrinology, Karolinska Institutet, Solna, Stockholm, Sweden
- S. Ramesh, V. Madhuri, Centre for Stem Cell Research, a Unit of InStem Bengaluru, Christian Medical College, Bagayam, Vellore, India
| | - Farasat Zaman
- S. Ramesh, F. Zaman, L. Sävendahl, Department of Women's and Children's Health and Paediatric Endocrinology, Karolinska Institutet, Solna, Stockholm, Sweden
| | - Vrisha Madhuri
- S. Ramesh, V. Madhuri, Paediatric Orthopaedics, Christian Medical College and Hospital, Vellore, India
- S. Ramesh, V. Madhuri, Centre for Stem Cell Research, a Unit of InStem Bengaluru, Christian Medical College, Bagayam, Vellore, India
| | - Lars Sävendahl
- S. Ramesh, F. Zaman, L. Sävendahl, Department of Women's and Children's Health and Paediatric Endocrinology, Karolinska Institutet, Solna, Stockholm, Sweden
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47
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Dong Y, Chen Y, Zhang L, Tian Z, Dong S. P2X7 receptor acts as an efficient drug target in regulating bone metabolism system. Biomed Pharmacother 2020; 125:110010. [PMID: 32187957 DOI: 10.1016/j.biopha.2020.110010] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Revised: 02/05/2020] [Accepted: 02/12/2020] [Indexed: 12/12/2022] Open
Abstract
Skeletal system is a highly dynamic system going through continuous resorption and reconstruction to maintain homeostasis, which is influenced by numerous factors. Once the balance is disrupted, various kinds of bone diseases may occur such as osteoporosis. It has been well known that ATP (adenosine triphosphate), an important signaling molecule, is important in maintaining the dynamic balance of bone matrix. ATP mainly functions through P2X receptors, a kind of ATP receptors expressed by various kinds of bone cells to regulate the whole network of skeleton system. Among P2X receptors, P2X7 plays a crucial role in bone since P2X7 is widely expressed by bone cells and the mutation of P2X7 receptor is associated with kinds of bone diseases. It's acknowledged that P2X7 acts as a potential therapeutic target for clinical treatment of bone-related diseases but further investigations are needed for the practical application. However, since P2X7 has a complicated effect in many aspects, the exact role of P2X7 in skeleton system is ambiguous. This review discusses the function of P2X7 in bone and other cells and their general effect on skeleton system, especially focusing on the possible clinical application for bone diseases.
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Affiliation(s)
- Yutong Dong
- Department of Biomedical Materials Science, Army Medical University, Chongqing, China; Battalion one of Basic Medical Sciences, Army Medical University, Chongqing, China
| | - Yueqi Chen
- Department of Biomedical Materials Science, Army Medical University, Chongqing, China; Department of Orthopedics, Southwest Hospital, Army medical university, Chongqing, China
| | - Lincheng Zhang
- Department of Biomedical Materials Science, Army Medical University, Chongqing, China; Battalion one of Basic Medical Sciences, Army Medical University, Chongqing, China
| | - Zhansong Tian
- Department of Biomedical Materials Science, Army Medical University, Chongqing, China
| | - Shiwu Dong
- Department of Biomedical Materials Science, Army Medical University, Chongqing, China; Department of Orthopedics, Southwest Hospital, Army medical university, Chongqing, China; State Key Laboratory of Trauma, Burns and Combined Injury, Army medical university, Chongqing, China.
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48
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Mousawi F, Peng H, Li J, Ponnambalam S, Roger S, Zhao H, Yang X, Jiang LH. Chemical activation of the Piezo1 channel drives mesenchymal stem cell migration via inducing ATP release and activation of P2 receptor purinergic signaling. Stem Cells 2020; 38:410-421. [PMID: 31746084 PMCID: PMC7064961 DOI: 10.1002/stem.3114] [Citation(s) in RCA: 65] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2018] [Revised: 08/02/2019] [Accepted: 09/01/2019] [Indexed: 12/12/2022]
Abstract
In this study, we examined the Ca2+‐permeable Piezo1 channel, a newly identified mechanosensing ion channel, in human dental pulp‐derived mesenchymal stem cells (MSCs) and hypothesized that activation of the Piezo1 channel regulates MSC migration via inducing ATP release and activation of the P2 receptor purinergic signaling. The Piezo1 mRNA and protein were readily detected in hDP‐MSCs from multiple donors and, consistently, brief exposure to Yoda1, the Piezo1 channel‐specific activator, elevated intracellular Ca2+ concentration. Yoda1‐induced Ca2+ response was inhibited by ruthenium red or GsMTx4, two Piezo1 channel inhibitors, and also by Piezo1‐specific siRNA. Brief exposure to Yoda1 also induced ATP release. Persistent exposure to Yoda1 stimulated MSC migration, which was suppressed by Piezo1‐specific siRNA, and also prevented by apyrase, an ATP scavenger, or PPADS, a P2 generic antagonist. Furthermore, stimulation of MSC migration induced by Yoda1 as well as ATP was suppressed by PF431396, a PYK2 kinase inhibitor, or U0126, an inhibitor of the mitogen‐activated protein kinase MEK/ERK signaling pathway. Collectively, these results suggest that activation of the Piezo1 channel stimulates MSC migration via inducing ATP release and subsequent activation of the P2 receptor purinergic signaling and downstream PYK2 and MEK/ERK signaling pathways, thus revealing novel insights into the molecular and signaling mechanisms regulating MSC migration. Such findings provide useful information for evolving a full understanding of MSC migration and homing and developing strategies to improve MSC‐based translational applications.
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Affiliation(s)
- Fatema Mousawi
- School of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds, Leeds, United Kingdom.,Department of Oral Biology, Faculty of Medicine and Health, University of Leeds, Leeds, United Kingdom
| | - Hongsen Peng
- School of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds, Leeds, United Kingdom.,Department of Oral Biology, Faculty of Medicine and Health, University of Leeds, Leeds, United Kingdom
| | - Jing Li
- Lingnan Medical Research Centre, School of Medicine, Guangzhou University of Chinese Medicine, Guangzhou, People's Republic of China
| | - Sreenivasan Ponnambalam
- School of Molecular and Cell Biology, Faculty of Biological Sciences, University of Leeds, Leeds, United Kingdom
| | - Sébastien Roger
- EA4245, Transplantation, Immunology and Inflammation, Faculty of Medicine, University of Tours, Tours, France
| | - Hucheng Zhao
- Institute of Biomechanics and Medical Engineering, Tsinghua University, Beijing, People's Republic of China
| | - Xuebin Yang
- Department of Oral Biology, Faculty of Medicine and Health, University of Leeds, Leeds, United Kingdom
| | - Lin-Hua Jiang
- School of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds, Leeds, United Kingdom.,EA4245, Transplantation, Immunology and Inflammation, Faculty of Medicine, University of Tours, Tours, France
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Cho W, Kim S, Jeong M, Park YM. Shockwaves Suppress Adipocyte Differentiation via Decrease in PPARγ. Cells 2020; 9:cells9010166. [PMID: 31936603 PMCID: PMC7017360 DOI: 10.3390/cells9010166] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2019] [Revised: 01/03/2020] [Accepted: 01/07/2020] [Indexed: 12/18/2022] Open
Abstract
Adipogenesis is a crucial cellular process that contributes to the expansion of adipose tissue in obesity. Shockwaves are mechanical stimuli that transmit signals to cause biological responses. The purpose of this study is to evaluate the effects of shockwaves on adipogenesis. We treated 3T3L-1 cells and human primary preadipocytes for differentiation with or without shockwaves. Western blots and quantitative real-time reverse transcriptase PCR (qRT-PCR) for adipocyte markers including peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT-enhancer-binding proteins (C/EBPα) were performed. Extracellular adenosine triphosphate (ATP) and intracellular cyclic adenosine monophosphate (cAMP) levels, which are known to affect adipocyte differentiation, were measured. Shockwave treatment decreased intracellular lipid droplet accumulation in primary human preadipocytes and 3T3-L1 cells after 11–12 days of differentiation. Levels of key adipogenic transcriptional factors PPARγ and/or C/EBPα were lower in shockwave-treated human primary preadipocytes and 3T3L-1 cells after 12–13 days of differentiation than in shockwave-untreated cells. Shockwave treatment induced release of extracellular ATP from preadipocytes and decreased intracellular cAMP levels. Shockwave-treated preadipocytes showed a higher level of β-catenin and less PPARγ expression than shockwave-untreated cells. Supplementation with 8-bromo-cAMP analog after shockwave treatment rescued adipocyte differentiation by preventing the effect of shockwaves on β-catenin, Wnt10b mRNA, and PPARγ expression. Low-energy shockwaves suppressed adipocyte differentiation by decreasing PPARγ. Our study suggests an insight into potential uses of shockwave-treatment for obesity.
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Pinto-Cardoso R, Pereira-Costa F, Pedro Faria J, Bandarrinha P, Bessa-Andrês C, Correia-de-Sá P, Bernardo Noronha-Matos J. Adenosinergic signalling in chondrogenesis and cartilage homeostasis: Friend or foe? Biochem Pharmacol 2019; 174:113784. [PMID: 31884043 DOI: 10.1016/j.bcp.2019.113784] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2019] [Accepted: 12/23/2019] [Indexed: 12/11/2022]
Abstract
Chondrocytes and their mesenchymal cell progenitors secrete a variety of bioactive molecules, including adenine nucleotides and nucleosides, but these molecules are not usually highlighted in review papers about the secretome of these cells. Ageing and inflammatory insults compromise chondrocytes ability to keep ATP/adenosine synthesis, release and turnover. Cartilage homeostasis depends on extracellular adenosine levels, which acting via four P1 purinoceptor subtypes modulates the release of pro-inflammatory mediators, including NO, PGE2 and several cytokines. Native articular cartilage is challenged by synovial fluid flow during normal joint motion transiently increasing ATP release and adenosine formation in the joint microenvironment. Excessive joint motion and shockwave trauma are deleterious to cartilage homeostasis due to HIF-1α overexpression, resulting in disproportionate ecto-5'-nucleotidase/CD73 production, adenosine accumulation and superfluous A2B receptors activation. Scarcity of data however exists on the putative interplay between coexistent high affinity (A2A and A3) and low affinity (A2B) adenosine receptors activation affecting stem cells fate towards preferential chondrogenic or osteogenic lineages in the human cartilage. Hints gathered in this commentary result mainly from studies using human immortalized cell lines and animal (e.g. rodent, equine, bovine) tissue samples. The available data point towards adenosine A2A and A3 receptors having cartilage protective roles, while excessive adenosine accumulation may be detrimental via low affinity A2B receptors activation, with little reference to the putative role of the adenosine forming enzyme ecto-5'-nucleotidase/CD73. Thus, emphasizing the multiple pathways responsible for controlling adenosine signalling in cartilage will certainly impact on the search for novel therapeutic targets for highly disabling articular disorders.
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Affiliation(s)
- Rui Pinto-Cardoso
- Laboratório de Farmacologia e Neurobiologia, Departamento de Imuno-Fisiologia e Farmacologia, Instituto de Ciências Biomédicas Abel Salazar - Universidade do Porto (ICBAS-UP), Portugal; Center for Drug Discovery and Innovative Medicines (MedInUP), Departamento de Imuno-Fisiologia e Farmacologia, Instituto de Ciências Biomédicas Abel Salazar - Universidade do Porto (ICBAS-UP), Portugal
| | - Flávio Pereira-Costa
- Laboratório de Farmacologia e Neurobiologia, Departamento de Imuno-Fisiologia e Farmacologia, Instituto de Ciências Biomédicas Abel Salazar - Universidade do Porto (ICBAS-UP), Portugal; Center for Drug Discovery and Innovative Medicines (MedInUP), Departamento de Imuno-Fisiologia e Farmacologia, Instituto de Ciências Biomédicas Abel Salazar - Universidade do Porto (ICBAS-UP), Portugal
| | - João Pedro Faria
- Laboratório de Farmacologia e Neurobiologia, Departamento de Imuno-Fisiologia e Farmacologia, Instituto de Ciências Biomédicas Abel Salazar - Universidade do Porto (ICBAS-UP), Portugal; Center for Drug Discovery and Innovative Medicines (MedInUP), Departamento de Imuno-Fisiologia e Farmacologia, Instituto de Ciências Biomédicas Abel Salazar - Universidade do Porto (ICBAS-UP), Portugal
| | - Patrícia Bandarrinha
- Laboratório de Farmacologia e Neurobiologia, Departamento de Imuno-Fisiologia e Farmacologia, Instituto de Ciências Biomédicas Abel Salazar - Universidade do Porto (ICBAS-UP), Portugal; Center for Drug Discovery and Innovative Medicines (MedInUP), Departamento de Imuno-Fisiologia e Farmacologia, Instituto de Ciências Biomédicas Abel Salazar - Universidade do Porto (ICBAS-UP), Portugal
| | - Catarina Bessa-Andrês
- Laboratório de Farmacologia e Neurobiologia, Departamento de Imuno-Fisiologia e Farmacologia, Instituto de Ciências Biomédicas Abel Salazar - Universidade do Porto (ICBAS-UP), Portugal; Center for Drug Discovery and Innovative Medicines (MedInUP), Departamento de Imuno-Fisiologia e Farmacologia, Instituto de Ciências Biomédicas Abel Salazar - Universidade do Porto (ICBAS-UP), Portugal
| | - Paulo Correia-de-Sá
- Laboratório de Farmacologia e Neurobiologia, Departamento de Imuno-Fisiologia e Farmacologia, Instituto de Ciências Biomédicas Abel Salazar - Universidade do Porto (ICBAS-UP), Portugal; Center for Drug Discovery and Innovative Medicines (MedInUP), Departamento de Imuno-Fisiologia e Farmacologia, Instituto de Ciências Biomédicas Abel Salazar - Universidade do Porto (ICBAS-UP), Portugal.
| | - José Bernardo Noronha-Matos
- Laboratório de Farmacologia e Neurobiologia, Departamento de Imuno-Fisiologia e Farmacologia, Instituto de Ciências Biomédicas Abel Salazar - Universidade do Porto (ICBAS-UP), Portugal; Center for Drug Discovery and Innovative Medicines (MedInUP), Departamento de Imuno-Fisiologia e Farmacologia, Instituto de Ciências Biomédicas Abel Salazar - Universidade do Porto (ICBAS-UP), Portugal.
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