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Tang L, Wang Y, Mao S, Yu Z, Chen Y, Xu X, Cai W, Lai K, Yang G, Huang T. Engineered bone-targeting apoptotic vesicles as a minimally invasive nanotherapy for heterotopic ossification. J Nanobiotechnology 2025; 23:348. [PMID: 40369573 PMCID: PMC12077018 DOI: 10.1186/s12951-025-03431-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2025] [Accepted: 05/01/2025] [Indexed: 05/16/2025] Open
Abstract
Heterotopic Ossification (HO), refers to pathological extra skeletal bone formation, and there are currently no reliable methods except surgery to reverse these unexpected calcified tissues. Apoptotic vesicles (ApoEVs) are membrane-bound vesicles released by apoptotic cells, which are involved in metabolism regulation and intercellular communication. Due to its superior trauma-healing ability, the hard palate mucosa is expected to become an essential resource for tissue engineering. This work presents a minimally invasive nanotherapy based on an engineered apoEV. Briefly, apoEVs were extracted from hard palate mucosa and engineered with bone-targeting peptide SDSSD to treat HO. This engineered apoEV not only can achieve directed localization of heterotopic bones but also has the compelling dual function of promoting osteoclastic differentiation while inhibiting osteogenic differentiation. The underlying mechanism involves the activation of Hippo and Notch pathways, as well as the regulation of pyrimidine metabolism. We envision that this engineered apoEV may be a feasible and effective strategy for reversing HO.
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Affiliation(s)
- Like Tang
- Stomatology Hospital, School of Stomatology, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province, Zhejiang University School of Medicine, Cancer Center of Zhejiang University, Hangzhou, 310000, China
| | - Yuchen Wang
- Stomatology Hospital, School of Stomatology, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province, Zhejiang University School of Medicine, Cancer Center of Zhejiang University, Hangzhou, 310000, China
| | - Shihua Mao
- Stomatology Hospital, School of Stomatology, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province, Zhejiang University School of Medicine, Cancer Center of Zhejiang University, Hangzhou, 310000, China
| | - Zhou Yu
- Stomatology Hospital, School of Stomatology, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province, Zhejiang University School of Medicine, Cancer Center of Zhejiang University, Hangzhou, 310000, China
| | - Yitong Chen
- Stomatology Hospital, School of Stomatology, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province, Zhejiang University School of Medicine, Cancer Center of Zhejiang University, Hangzhou, 310000, China
| | - Xiaoqiao Xu
- The Affiliated Stomatology Hospital, Zhejiang University School of Medicine, Hangzhou, 310000, China
| | - Wenjin Cai
- Stomatology Hospital, School of Stomatology, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province, Zhejiang University School of Medicine, Cancer Center of Zhejiang University, Hangzhou, 310000, China
| | - Kaichen Lai
- Stomatology Hospital, School of Stomatology, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province, Zhejiang University School of Medicine, Cancer Center of Zhejiang University, Hangzhou, 310000, China
- Department of Implantology, The Affiliated Stomatology Hospital, Zhejiang University School of Medicine, Hangzhou, 310000, China
| | - Guoli Yang
- Stomatology Hospital, School of Stomatology, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province, Zhejiang University School of Medicine, Cancer Center of Zhejiang University, Hangzhou, 310000, China.
- Department of Implantology, The Affiliated Stomatology Hospital, Zhejiang University School of Medicine, Hangzhou, 310000, China.
| | - Tingben Huang
- Stomatology Hospital, School of Stomatology, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province, Zhejiang University School of Medicine, Cancer Center of Zhejiang University, Hangzhou, 310000, China.
- Department of Implantology, The Affiliated Stomatology Hospital, Zhejiang University School of Medicine, Hangzhou, 310000, China.
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Xu C, Qiu S, Yuan Z, Qiu C, Xu W, Guo J, Wen G, Liu S, Yan W, Xu H, Hou H, Yang D. Biomimetic Microstructured Scaffold with Release of Re-Modified Teriparatide for Osteoporotic Tendon-to-Bone Regeneration via Balancing Bone Homeostasis. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2500144. [PMID: 40091692 PMCID: PMC12079530 DOI: 10.1002/advs.202500144] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/03/2025] [Revised: 02/11/2025] [Indexed: 03/19/2025]
Abstract
Osteoporotic tendon-to-bone interface healing is challenging, with a high surgical repair failure rate of up to 68%. Conventional tissue engineering approaches have primarily focused on promoting interface healing by stimulating regeneration in either the tendon or bone. However, these methods often fall short of achieving optimal therapeutic outcomes due to their neglect of balancing bone homeostasis and remodeling the microstructure at the osteoporotic tendon-to-bone interface. Herein, a series of site-specific functional modifications are carried out on teriparatide to develop recombinant human parathyroid hormone (R-PTH). A biomimetic microstructured reconstruction scaffold (BMRP) is constructed using a decalcified mussel shell scaffold, pre-gel, and R-PTH. The BMRP mimics the microstructures of the native tendon-to-bone interface and restores the original structure of the interface tissue by repairing injured cells, balancing bone homeostasis, and remodeling the microstructure of the osteoporotic tendon-to-bone interface. In an osteoporotic rotator cuff tear model, BMRP is in situ implanted at the injured site, resulting in structural reconstruction and functional recovery. The BMRP demonstrates excellent repair effects, representing a novel therapeutical alternative for treating osteoporotic tendon-to-bone injury potential for clinical application.
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Affiliation(s)
- Chengzhong Xu
- Department of Orthopaedics‐Spine SurgeryNanfang HospitalSouthern Medical University1838 North Guangzhou AveGuangzhou510515P. R. China
- Guangdong Provincial Key Laboratory of Construction and Detection in Tissue EngineeringSchool of Basic Medical SciencesSouthern Medical UniversityGuangzhou510515P. R. China
| | - Sijie Qiu
- Department of StomatologyNanfang HospitalSouthern Medical UniversityGuangzhou510515P. R. China
| | - Zhigen Yuan
- Department of Orthopaedics‐Spine SurgeryNanfang HospitalSouthern Medical University1838 North Guangzhou AveGuangzhou510515P. R. China
| | - Chongyin Qiu
- Guangdong Provincial Key Laboratory of Construction and Detection in Tissue EngineeringSchool of Basic Medical SciencesSouthern Medical UniversityGuangzhou510515P. R. China
| | - Wenyu Xu
- Department of Orthopaedics‐Spine SurgeryNanfang HospitalSouthern Medical University1838 North Guangzhou AveGuangzhou510515P. R. China
| | - Jialiang Guo
- Department of Orthopaedics‐Spine SurgeryNanfang HospitalSouthern Medical University1838 North Guangzhou AveGuangzhou510515P. R. China
| | - Gen Wen
- Department of Orthopaedics‐Spine SurgeryNanfang HospitalSouthern Medical University1838 North Guangzhou AveGuangzhou510515P. R. China
| | - Shuai Liu
- Guangdong Provincial Key Laboratory of Construction and Detection in Tissue EngineeringSchool of Basic Medical SciencesSouthern Medical UniversityGuangzhou510515P. R. China
| | - Wenjuan Yan
- Department of StomatologyNanfang HospitalSouthern Medical UniversityGuangzhou510515P. R. China
| | - Haibing Xu
- Guangdong‐Hong Kong‐Macao Greater Bay Area Center for Brain Science and Brain‐Inspired IntelligenceDepartment of NeurobiologySchool of Basic Medical SciencesSouthern Medical UniversityGuangzhou510515P. R. China
| | - Honghao Hou
- Guangdong Provincial Key Laboratory of Construction and Detection in Tissue EngineeringSchool of Basic Medical SciencesSouthern Medical UniversityGuangzhou510515P. R. China
| | - Dehong Yang
- Department of Orthopaedics‐Spine SurgeryNanfang HospitalSouthern Medical University1838 North Guangzhou AveGuangzhou510515P. R. China
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Hopkinson M, Pitsillides AA. Extracellular matrix: Dystroglycan interactions-Roles for the dystrophin-associated glycoprotein complex in skeletal tissue dynamics. Int J Exp Pathol 2025; 106:e12525. [PMID: 39923120 PMCID: PMC11807010 DOI: 10.1111/iep.12525] [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: 06/11/2024] [Revised: 12/23/2024] [Accepted: 12/29/2024] [Indexed: 02/10/2025] Open
Abstract
Contributions made by the dystrophin-associated glycoprotein complex (DGC) to cell-cell and cell-extracellular matrix (ECM) interactions are vital in development, homeostasis and pathobiology. This review explores how DGC functions may extend to skeletal pathophysiology by appraising the known roles of its major ECM ligands, and likely associated DGC signalling pathways, in regulating cartilage and bone cell behaviour and emergent skeletal phenotypes. These considerations will be contextualised by highlighting the potential of studies into the role of the DGC in isolated chondrocytes, osteoblasts and osteoclasts, and by fuller deliberation of skeletal phenotypes that may emerge in very young mice lacking vital, yet diverse core elements of the DGC. Our review points to roles for individual DGC components-including the glycosylation of dystroglycan itself-beyond the establishment of membrane stability which clearly accounts for severe muscle phenotypes in muscular dystrophy. It implies that the short stature, low bone mineral density, poor bone health and greater fracture risk in these patients, which has been attributed due to primary deficiencies in muscle-evoked skeletal loading, may instead arise due to primary roles for the DGC in controlling skeletal tissue (re)modelling.
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Affiliation(s)
- Mark Hopkinson
- Skeletal Biology Group, Comparative Biomedical SciencesRoyal Veterinary CollegeLondonUK
| | - Andrew A. Pitsillides
- Skeletal Biology Group, Comparative Biomedical SciencesRoyal Veterinary CollegeLondonUK
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Dilawar M, Yu X, Jin Y, Yang J, Lin S, Liao J, Dai Q, Zhang X, Nisar MF, Chen G. Notch signaling pathway in osteogenesis, bone development, metabolism, and diseases. FASEB J 2025; 39:e70417. [PMID: 39985304 DOI: 10.1096/fj.202402545r] [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: 10/21/2024] [Revised: 01/18/2025] [Accepted: 02/14/2025] [Indexed: 02/24/2025]
Abstract
The skeletal system provides vital importance to support organ development and functions. The Notch signaling pathway possesses well-established functions in organ development and cellular homeostasis. The Notch signaling pathway comprises five typical ligands (JAG1, JAG2, DLL1, DLL3, and DLL4), four receptors (Notch1-4), and four intracellular domains (NICD1-4). Each component of the Notch signaling pathway has been demonstrated to be fundamental in osteoblast differentiation and bone formation. The dysregulation in the Notch signaling pathway is highly linked with skeletal disorders or diseases at the developmental and postnatal stages. Recent studies have highlighted the importance of the elements of the Notch signaling pathway in the skeletal system, as well as its interaction with signaling, such as Wnt/β-catenin, BMP, TGF-β, FGF, autophagy, and hedgehog (Hh) to construct a potential gene regulatory network to orchestrate osteogenesis and ossification. Our review has provided a comprehensive summary of the Notch signaling pathway in the skeletal system, as well as the insights targeting Notch signaling for innovative potential drug discovery targets or therapeutic interventions to treat bone disorders, such as osteoporosis and osteoarthritis. An in-depth molecular mechanistic strategy to modulate the Notch signaling pathway and its associated signaling pathway will be encouraged for consideration to trigger enhanced therapeutic approaches for bone disorders by defining Notch-regulating drugs for clinical use.
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Affiliation(s)
- Muhammad Dilawar
- Department of Biopharmaceutics, Zhejiang Provincial Engineering Research Center of New Technologies and Applications for Targeted Therapy of Major Diseases, College of Life Science and Medicine, Zhejiang Sci-Tech University, Hangzhou, China
| | - Xuan Yu
- Department of Biopharmaceutics, Zhejiang Provincial Engineering Research Center of New Technologies and Applications for Targeted Therapy of Major Diseases, College of Life Science and Medicine, Zhejiang Sci-Tech University, Hangzhou, China
| | - Yuanyuan Jin
- Department of Biopharmaceutics, Zhejiang Provincial Engineering Research Center of New Technologies and Applications for Targeted Therapy of Major Diseases, College of Life Science and Medicine, Zhejiang Sci-Tech University, Hangzhou, China
| | - Jing Yang
- Department of Biopharmaceutics, Zhejiang Provincial Engineering Research Center of New Technologies and Applications for Targeted Therapy of Major Diseases, College of Life Science and Medicine, Zhejiang Sci-Tech University, Hangzhou, China
| | - Sisi Lin
- Department of Biopharmaceutics, Zhejiang Provincial Engineering Research Center of New Technologies and Applications for Targeted Therapy of Major Diseases, College of Life Science and Medicine, Zhejiang Sci-Tech University, Hangzhou, China
| | - Junguang Liao
- Department of Biopharmaceutics, Zhejiang Provincial Engineering Research Center of New Technologies and Applications for Targeted Therapy of Major Diseases, College of Life Science and Medicine, Zhejiang Sci-Tech University, Hangzhou, China
| | - Qi Dai
- Department of Biopharmaceutics, Zhejiang Provincial Engineering Research Center of New Technologies and Applications for Targeted Therapy of Major Diseases, College of Life Science and Medicine, Zhejiang Sci-Tech University, Hangzhou, China
| | - Xingen Zhang
- Department of Orthopedics, Jiaxing Key Laboratory for Minimally Invasive Surgery in Orthopaedics & Skeletal Regenerative Medicine, Zhejiang Rongjun Hospital, Jiaxing, China
| | - Muhammad Farrukh Nisar
- Department of Physiology & Biochemistry, Cholistan University of Veterinary and Animal Sciences, Bahawalpur, Pakistan
- Ministry of Education and Jiangxi Key Laboratory of Crop Physiology, Ecology and Genetic Breeding, Jiangxi Agricultural University, Nanchang, China
| | - Guiqian Chen
- Department of Biopharmaceutics, Zhejiang Provincial Engineering Research Center of New Technologies and Applications for Targeted Therapy of Major Diseases, College of Life Science and Medicine, Zhejiang Sci-Tech University, Hangzhou, China
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5
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Cao B, Wu X, Zhou C, Chen H, Xue D, Pan Z. Salvianolic acid A promotes bone-fracture healing via balancing osteoblast and osteoclast differentiation. FASEB J 2025; 39:e70364. [PMID: 39878631 DOI: 10.1096/fj.202402515r] [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: 10/19/2024] [Revised: 01/06/2025] [Accepted: 01/21/2025] [Indexed: 01/31/2025]
Abstract
Nonunion is a significant complication in fracture management for surgeons. Salvianolic acid A (SAA), derived from the traditional Chinese plant Salviae miltiorrhizae Bunge (Danshen), exhibits notable anti-inflammatory and antioxidant properties. Although studies have demonstrated its ability to promote osteogenic differentiation, the exact mechanism of action remains unclear. This study investigated the effects of various SAA concentrations on the osteogenic differentiation of mouse-derived bone marrow mesenchymal stem cells (mBMSCs) and the osteoclastic differentiation of bone marrow-derived macrophages. Our findings indicate that SAA promotes the osteogenic differentiation of mBMSCs in a concentration-dependent manner, primarily by inhibiting the Notch1 signaling pathway. Notably, the administration of two Notch1 agonists (Jagged-1 and VPA) inhibited the effects of SAA on osteogenic differentiation. Additionally, SAA facilitated the autophagic degradation of NICD1, further enhancing osteogenic differentiation. Furthermore, SAA also dose-dependently inhibited the osteoclastic differentiation of bone marrow-derived macrophages, which is linked to its suppression of NF-κB signaling pathways. In a fracture model, SAA demonstrated a capacity to promote healing. In conclusion, SAA enhances bone fracture healing by balancing osteoblast and osteoclast differentiation.
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Affiliation(s)
- Binhao Cao
- Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China
- Orthopedics Research Institute of Zhejiang University, Hangzhou, People's Republic of China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, People's Republic of China
- Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou, People's Republic of China
| | - Xiaoyong Wu
- Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China
- Orthopedics Research Institute of Zhejiang University, Hangzhou, People's Republic of China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, People's Republic of China
- Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou, People's Republic of China
| | - Chengwei Zhou
- Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China
- Orthopedics Research Institute of Zhejiang University, Hangzhou, People's Republic of China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, People's Republic of China
- Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou, People's Republic of China
| | - Hongyu Chen
- Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China
- Orthopedics Research Institute of Zhejiang University, Hangzhou, People's Republic of China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, People's Republic of China
- Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou, People's Republic of China
| | - Deting Xue
- Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China
- Orthopedics Research Institute of Zhejiang University, Hangzhou, People's Republic of China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, People's Republic of China
- Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou, People's Republic of China
| | - Zhijun Pan
- Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China
- Orthopedics Research Institute of Zhejiang University, Hangzhou, People's Republic of China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, People's Republic of China
- Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou, People's Republic of China
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6
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Jin Y, Son Y, Song I, Chung YS, Choi YJ. Orphan nuclear receptor NR4A1 regulates both osteoblastogenesis and adipogenesis in human mesenchymal stem cells. Mol Med Rep 2025; 31:3. [PMID: 39422036 PMCID: PMC11544528 DOI: 10.3892/mmr.2024.13368] [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: 01/16/2024] [Accepted: 09/19/2024] [Indexed: 10/19/2024] Open
Abstract
The nuclear receptor subfamily 4 group A member 1 (NR4A1) gene plays a crucial role in both osteoporosis and adipogenesis. The present study investigated the mechanisms by which NR4A1 influences osteoblastogenesis and adipogenesis in human bone marrow‑derived mesenchymal stem cells (BMD‑MSCs). NR4A1 was overexpressed or knocked down in mouse MC3T3‑E1 osteoblast cells and 3T3‑L1 adipocyte cells, as well as in PCS‑500‑012, a BMD‑MSC line. The alkaline phosphatase (ALP) assay and Alizarin Red S staining were performed using MC3T3‑E1 and BMD‑MSCs to assess ALP activity and mineralization, while Oil Red O staining was used to assess the lipid content in 3T3‑L1 cells and BMD‑MSCs. Total RNA was isolated from control, NR4A1‑overexpressing and NR4A1 small interfering RNA (siRNA; siNR4A1)‑treated BMD‑MSCs. RNA sequencing (RNA‑seq) was performed to identify differentially expressed genes, followed by ingenuity pathway analysis (IPA) to determine the role of NR4A1 in osteoblastogenesis and adipogenesis. NR4A1 or Nr4a1 knockdown tended to increase ALP activity and significantly increased calcification in BMD‑MSCs (P<0.005) and MC3T3‑E1 cells (P<0.005), respectively. By contrast, NR4A1 or Nr4a1 overexpression significantly decreased ALP activity and calcification. NR4A1 or Nr4a1 knockdown and overexpression significantly decreased and increased adipogenesis, respectively, in BMD‑MSCs (P<0.005 and <0.05, respectively) and 3T3‑L1 cells (P<0.005 in both). Treatments of BMD‑MSCs with an NR4A1 antagonist, 1,1‑bis(3'‑indolyl)‑1‑(p‑hydroxyphenyl) methane and siNR4A1 showed similar results. RNA‑seq and IPA in control, NR4A1 knockdown and NR4A1 overexpressing cells indicated that Notch signaling mediated the effects of NR4A1 in osteoblastogenesis and adipogenesis. Expression of mastermind‑like transcriptional coactivator 3 was reduced in the Notch signaling pathway in cells treated with siNR4A1. In conclusion, NR4A1 suppressed osteoblastogenesis and promotes adipogenesis in human BMD‑MSCs. The present study also suggested that NR4A1 plays a role in the progression of osteoporosis and adipogenesis by modulating the Notch signaling cascade.
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Affiliation(s)
- Yilan Jin
- Department of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon, Gyeonggi-do 16499, Republic of Korea
- Ajou Institute on Aging, Ajou University Medical Center, Suwon, Gyeonggi-do 16499, Republic of Korea
| | - Youngho Son
- Department of Physiology, Ajou University School of Medicine, Suwon, Gyeonggi-do 16499, Republic of Korea
| | - Insun Song
- Department of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon, Gyeonggi-do 16499, Republic of Korea
- Ajou Institute on Aging, Ajou University Medical Center, Suwon, Gyeonggi-do 16499, Republic of Korea
| | - Yoon-Sok Chung
- Department of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon, Gyeonggi-do 16499, Republic of Korea
- Ajou Institute on Aging, Ajou University Medical Center, Suwon, Gyeonggi-do 16499, Republic of Korea
| | - Yong Jun Choi
- Department of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon, Gyeonggi-do 16499, Republic of Korea
- Ajou Institute on Aging, Ajou University Medical Center, Suwon, Gyeonggi-do 16499, Republic of Korea
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Al-Shibli R, AlSuleimani M, Ahmed I, Al Lawati A, Das S. Association of miRNA and Bone Tumors: Future Therapeutic Inroads. Curr Med Chem 2025; 32:1103-1120. [PMID: 38299295 DOI: 10.2174/0109298673284932231226110754] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2023] [Revised: 11/24/2023] [Accepted: 11/30/2023] [Indexed: 02/02/2024]
Abstract
Small endogenous non-coding RNA molecules known as micro-ribonucleic acids (miRNAs) control post-transcriptional gene regulation. A change in miRNA expression is related to various diseases, including bone tumors. Benign bone tumors are categorized based on matrix production and predominant cell type. Osteochondromas and giant cell tumors are among the most common bone tumors. Interestingly, miRNAs can function as either tumor suppressor genes or oncogenes, thereby determining the fate of a tumor. In the present review, we discuss various bone tumors with regard to their prognosis, pathogenesis, and diagnosis. The association between miRNAs and bone tumors, such as osteosarcoma, Ewing's sarcoma, chondrosarcoma, and giant-cell tumors, is also discussed. Moreover, miRNA may play an important role in tumor proliferation, growth, and metastasis. Knowledge of the dysregulation, amplification, and deletion of miRNA can be beneficial for the treatment of various bone cancers. The miRNAs could be beneficial for prognosis, treatment, future drug design, and treatment of resistant cases of bone cancer.
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Affiliation(s)
- Rashid Al-Shibli
- Department of Medical, Sultan Qaboos University Hospital, Muscat, 123, Oman
| | | | - Ibrahim Ahmed
- Department of Medical, Sultan Qaboos University Hospital, Muscat, 123, Oman
| | - Abdullah Al Lawati
- Department of Medical, Sultan Qaboos University Hospital, Muscat, 123, Oman
| | - Srijit Das
- Department of Human & Clinical Anatomy, Sultan Qaboos University, Muscat, 123, Oman
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Bertels JC, He G, Long F. Metabolic reprogramming in skeletal cell differentiation. Bone Res 2024; 12:57. [PMID: 39394187 PMCID: PMC11470040 DOI: 10.1038/s41413-024-00374-0] [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: 05/16/2024] [Revised: 09/04/2024] [Accepted: 09/05/2024] [Indexed: 10/13/2024] Open
Abstract
The human skeleton is a multifunctional organ made up of multiple cell types working in concert to maintain bone and mineral homeostasis and to perform critical mechanical and endocrine functions. From the beginning steps of chondrogenesis that prefigures most of the skeleton, to the rapid bone accrual during skeletal growth, followed by bone remodeling of the mature skeleton, cell differentiation is integral to skeletal health. While growth factors and nuclear proteins that influence skeletal cell differentiation have been extensively studied, the role of cellular metabolism is just beginning to be uncovered. Besides energy production, metabolic pathways have been shown to exert epigenetic regulation via key metabolites to influence cell fate in both cancerous and normal tissues. In this review, we will assess the role of growth factors and transcription factors in reprogramming cellular metabolism to meet the energetic and biosynthetic needs of chondrocytes, osteoblasts, or osteoclasts. We will also summarize the emerging evidence linking metabolic changes to epigenetic modifications during skeletal cell differentiation.
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Affiliation(s)
- Joshua C Bertels
- Department of Surgery, Translational Research Program in Pediatric Orthopedics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - Guangxu He
- Department of Surgery, Translational Research Program in Pediatric Orthopedics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA
- Department of Orthopedics, The Second Xiangya Hospital, Changsha, Hunan, China
| | - Fanxin Long
- Department of Surgery, Translational Research Program in Pediatric Orthopedics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
- Department of Orthopedic Surgery, University of Pennsylvania, Philadelphia, PA, USA.
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9
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Aliyeva L, Ongen YD, Eren E, Sarisozen MB, Alemdar A, Temel SG, Sag SO. Genotype and Phenotype Correlation of Patients with Osteogenesis Imperfecta. J Mol Diagn 2024; 26:754-769. [PMID: 39025364 DOI: 10.1016/j.jmoldx.2024.05.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2023] [Revised: 04/17/2024] [Accepted: 05/16/2024] [Indexed: 07/20/2024] Open
Abstract
Osteogenesis imperfecta (OI) is the most common inherited connective tissue disease of the bone, characterized by recurrent fractures and deformities. In patients displaying the OI phenotype, genotype-phenotype correlation is used to screen multiple genes swiftly, identify new variants, and distinguish between differential diagnoses and mild subtypes. This study evaluated variants identified through next-generation sequencing in 58 patients with clinical characteristics indicative of OI. The cohort included 18 adults, 37 children, and 3 fetuses. Clinical classification revealed 25 patients as OI type I, three patients as OI type II, 18 as OI type III, and 10 as OI type IV. Fifteen variants in COL1A1 were detected in 19 patients, 9 variants in COL1A2 (n = 19), 5 variants in LEPRE1/P3H1 (n = 7), 3 variants in FKBP10 (n = 4), 3 variants in SERPINH1 (n = 2), 1 variant in IFITM5 (n = 1), and 1 variant in PLS3 (n = 1). In total, 37 variants (18 pathogenic, 14 likely pathogenic, and 5 variants of uncertain significance), including 16 novel variants, were identified in 43 (37 probands, 6 family members) of the 58 patients analyzed. This study highlights the efficacy of panel testing in the molecular diagnosis of OI, the significance of the next-generation sequencing technique, and the importance of genotype-phenotype correlation.
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Affiliation(s)
- Lamiya Aliyeva
- Department of Medical Genetics, Faculty of Medicine, Bursa Uludag University, Bursa, Turkey; Department of Medical Genetics, Atakent Hospital, Acibadem Health Group, Istanbul, Türkiye
| | - Yasemin Denkboy Ongen
- Department of Pediatric Endocrinology, Faculty of Medicine, Bursa Uludag University, Bursa, Turkey
| | - Erdal Eren
- Department of Pediatric Endocrinology, Faculty of Medicine, Bursa Uludag University, Bursa, Turkey
| | - Mehmet B Sarisozen
- Department of Orthopaedics and Traumatology, Faculty of Medicine, Bursa Uludag University, Bursa, Turkey
| | - Adem Alemdar
- Department of Translational Medicine, Health Sciences Institute, Bursa Uludag University, Bursa, Türkiye
| | - Sehime G Temel
- Department of Medical Genetics, Faculty of Medicine, Bursa Uludag University, Bursa, Turkey; Department of Histology and Embryology, Faculty of Medicine, Bursa Uludag University, Bursa, Turkey; Department of Translational Medicine, Health Sciences Institute, Bursa Uludag University, Bursa, Türkiye.
| | - Sebnem Ozemri Sag
- Department of Medical Genetics, Faculty of Medicine, Bursa Uludag University, Bursa, Turkey.
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10
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Zhou L, Huang C, HuangFu C, Shen P, Hu Y, Wang N, Li G, Deng H, Xia T, Zhou Y, Li J, Bai Z, Zhou W, Gao Y. Low-dose radiation-induced SUMOylation of NICD1 negatively regulates osteogenic differentiation in BMSCs. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2024; 282:116655. [PMID: 38968871 DOI: 10.1016/j.ecoenv.2024.116655] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Revised: 06/24/2024] [Accepted: 06/26/2024] [Indexed: 07/07/2024]
Abstract
Various biological effects of ionizing radiation, especially continuous exposure to low-dose radiation (LDR), have attracted considerable attention. Impaired bone structure caused by LDR has been reported, but little is known about the mechanism involved in the disruption of bone metabolism. In this study, given that LDR was found to (at a cumulative dose of 0.10 Gy) disturb the serum Mg2+ level and Notch1 signal in the mouse femur tissues, the effects of LDR on osteogenesis and the underlying molecular mechanisms were investigated based on an in vitro culture system for bone marrow stromal cells (BMSCs). Our data showed that cumulative LDR suppressed the osteogenic potential in BMSCs as a result of upregulation of Notch1 signaling. Further analyses indicated that the upregulation of NICD1 (Notch1 intracellular domain), the key intracellular domain for Notch1 signaling, under LDR was a consequence of enhanced protein stabilization caused by SUMOylation (small ubiquitin-like modification). Specifically, the downregulation of SENP1 (sentrin/SUMO-specific protease 1) expression induced by LDR enhanced the SUMOylation of NICD1, causing the accumulation of Notch1 signaling, which eventually inhibited the osteogenic potential of BMSCs. In conclusion, this work expounded on the mechanisms underlying the impacts of LDR on bone metabolism and shed light on the research on bone regeneration under radiation.
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Affiliation(s)
- Lei Zhou
- Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China; Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing 100850, China
| | - Congshu Huang
- Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China; Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing 100850, China
| | - Chaoji HuangFu
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing 100850, China
| | - Pan Shen
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing 100850, China
| | - Yangyi Hu
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing 100850, China
| | - Ningning Wang
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing 100850, China
| | - Gaofu Li
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing 100850, China
| | - Huifang Deng
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing 100850, China
| | - Tiantian Xia
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing 100850, China
| | - Yongqiang Zhou
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing 100850, China
| | - Jiamiao Li
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing 100850, China
| | - Zhijie Bai
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing 100850, China.
| | - Wei Zhou
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing 100850, China.
| | - Yue Gao
- Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China; Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing 100850, China.
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11
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Lai Z, Shu Q, Song Y, Tang A, Tian J. Effect of DNA methylation on the osteogenic differentiation of mesenchymal stem cells: concise review. Front Genet 2024; 15:1429844. [PMID: 39015772 PMCID: PMC11250479 DOI: 10.3389/fgene.2024.1429844] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Accepted: 06/10/2024] [Indexed: 07/18/2024] Open
Abstract
Mesenchymal stem cells (MSCs) have promising potential for bone tissue engineering in bone healing and regeneration. They are regarded as such due to their capacity for self-renewal, multiple differentiation, and their ability to modulate the immune response. However, changes in the molecular pathways and transcription factors of MSCs in osteogenesis can lead to bone defects and metabolic bone diseases. DNA methylation is an epigenetic process that plays an important role in the osteogenic differentiation of MSCs by regulating gene expression. An increasing number of studies have demonstrated the significance of DNA methyltransferases (DNMTs), Ten-eleven translocation family proteins (TETs), and MSCs signaling pathways about osteogenic differentiation in MSCs. This review focuses on the progress of research in these areas.
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Affiliation(s)
- Zhihao Lai
- Department of Rehabilitation Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Qing Shu
- Department of Rehabilitation Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Yue Song
- Department of Rehabilitation Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China
- College of Sports Medicine, Wuhan Sports University, Wuhan, China
| | - Ao Tang
- Department of Rehabilitation Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China
- College of Sports Medicine, Wuhan Sports University, Wuhan, China
| | - Jun Tian
- Department of Rehabilitation Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China
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12
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Chen J, Yu L, Gao T, Dong X, Li S, Liu Y, Yang J, Xia K, Yu Y, Li Y, Wang S, Fan Z, Deng H, Guo W. Nanofiber-induced hierarchically-porous magnesium phosphate bone cements accelerate bone regeneration by inhibiting Notch signaling. Bioact Mater 2024; 37:459-476. [PMID: 38698920 PMCID: PMC11063995 DOI: 10.1016/j.bioactmat.2024.03.021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2023] [Revised: 03/11/2024] [Accepted: 03/15/2024] [Indexed: 05/05/2024] Open
Abstract
Magnesium phosphate bone cements (MPC) have been recognized as a viable alternative for bone defect repair due to their high mechanical strength and biodegradability. However, their poor porosity and permeability limit osteogenic cell ingrowth and vascularization, which is critical for bone regeneration. In the current study, we constructed a novel hierarchically-porous magnesium phosphate bone cement by incorporating extracellular matrix (ECM)-mimicking electrospun silk fibroin (SF) nanofibers. The SF-embedded MPC (SM) exhibited a heterogeneous and hierarchical structure, which effectively facilitated the rapid infiltration of oxygen and nutrients as well as cell ingrowth. Besides, the SF fibers improved the mechanical properties of MPC and neutralized the highly alkaline environment caused by excess magnesium oxide. Bone marrow stem cells (BMSCs) adhered excellently on SM, as illustrated by formation of more pseudopodia. CCK8 assay showed that SM promoted early proliferation of BMSCs. Our study also verified that SM increased the expression of OPN, RUNX2 and BMP2, suggesting enhanced osteogenic differentiation of BMSCs. We screened for osteogenesis-related pathways, including FAK signaing, Wnt signaling and Notch signaling, and found that SM aided in the process of bone regeneration by suppressing the Notch signaling pathway, proved by the downregulation of NICD1, Hes1 and Hey2. In addition, using a bone defect model of rat calvaria, the study revealed that SM exhibited enhanced osteogenesis, bone ingrowth and vascularization compared with MPC alone. No adverse effect was found after implantation of SM in vivo. Overall, our novel SM exhibited promising prospects for the treatment of critical-sized bone defects.
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Affiliation(s)
- Jingteng Chen
- Department of Spine Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, China
| | - Ling Yu
- Department of Spine Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, China
| | - Tian Gao
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Bone and Soft Tissue Tumor, Peking University Cancer Hospital and Institute, Beijing, 100142, China
| | - Xiangyang Dong
- Hubei Key Laboratory of Biomass Resource Chemistry and Environmental Biotechnology, Hubei International Scientific and Technological Cooperation Base of Sustainable Resource and Energy, School of Resource and Environmental Science, Wuhan University, Wuhan, 430079, China
| | - Shiyu Li
- Department of Spine Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, China
| | - Yinchu Liu
- Department of Spine Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, China
| | - Jian Yang
- Department of Spine Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, China
| | - Kezhou Xia
- Department of Spine Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, China
| | - Yaru Yu
- Department of Spine Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, China
| | - Yingshuo Li
- Department of Spine Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, China
| | - Sen Wang
- Department of Spine Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, China
| | - ZhengFu Fan
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Bone and Soft Tissue Tumor, Peking University Cancer Hospital and Institute, Beijing, 100142, China
| | - Hongbing Deng
- Hubei Key Laboratory of Biomass Resource Chemistry and Environmental Biotechnology, Hubei International Scientific and Technological Cooperation Base of Sustainable Resource and Energy, School of Resource and Environmental Science, Wuhan University, Wuhan, 430079, China
| | - Weichun Guo
- Department of Spine Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, China
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13
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Andrique C, Bonnet AL, Dang J, Lesieur J, Krautzberger AM, Baroukh B, Torrens C, Sadoine J, Schmitt A, Rochefort GY, Bardet C, Six I, Houillier P, Tharaux PL, Schrewe H, Gaucher C, Chaussain C. Vasorin as an actor of bone turnover? J Cell Physiol 2024; 239:e31257. [PMID: 38504496 DOI: 10.1002/jcp.31257] [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: 10/02/2023] [Revised: 03/04/2024] [Accepted: 03/07/2024] [Indexed: 03/21/2024]
Abstract
Bone diseases are increasing with aging populations and it is important to identify clues to develop innovative treatments. Vasn, which encodes vasorin (Vasn), a transmembrane protein involved in the pathophysiology of several organs, is expressed during the development in intramembranous and endochondral ossification zones. Here, we studied the impact of Vasn deletion on the osteoblast and osteoclast dialog through a cell Coculture model. In addition, we explored the bone phenotype of Vasn KO mice, either constitutive or tamoxifen-inducible, or with an osteoclast-specific deletion. First, we show that both osteoblasts and osteoclasts express Vasn. Second, we report that, in both KO mouse models but not in osteoclast-targeted KO mice, Vasn deficiency was associated with an osteopenic bone phenotype, due to an imbalance in favor of osteoclastic resorption. Finally, through the Coculture experiments, we identify a dysregulation of the Wnt/β-catenin pathway together with an increase in RANKL release by osteoblasts, which led to an enhanced osteoclast activity. This study unravels a direct role of Vasn in bone turnover, introducing a new biomarker or potential therapeutic target for bone pathologies.
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Affiliation(s)
| | - Anne Laure Bonnet
- Université Paris Cité, Montrouge, France
- AP-HP, Services de médecine bucco-dentaire: GH Nord - Université Paris Cité, GH Sorbonne Université, GH Henri Mondor, Paris, France
| | - Julien Dang
- Paris Cardiovascular Research Centre - PARCC, Université Paris Cité, Inserm, Paris, France
| | | | - A Michaela Krautzberger
- Department of Developmental Genetics, Max Planck Institute for Molecular Genetics, Berlin, Germany
| | | | | | | | - Alain Schmitt
- Université Paris Cité, Institut Cochin, INSERM U1016, CNRS UMR8104, Paris, France
| | | | | | - Isabelle Six
- URP 7517 UPJV, Pathophysiological Mechanisms and Consequences of Cardiovascular Calcifications (MP3CV), Jules Verne University of Picardie, Amiens, France
| | - Pascal Houillier
- Centre de Recherche des Cordeliers, INSERM U1138, Sorbonne Université, Université Paris Cité, Paris, France
- AP-HP, Explorations fonctionnelles rénales, Physiologie, Hôpital européen Georges-Pompidou, Paris, France
| | - Pierre Louis Tharaux
- Paris Cardiovascular Research Centre - PARCC, Université Paris Cité, Inserm, Paris, France
| | - Heinrich Schrewe
- Department of Developmental Genetics, Max Planck Institute for Molecular Genetics, Berlin, Germany
| | - Celine Gaucher
- Université Paris Cité, Montrouge, France
- AP-HP, Services de médecine bucco-dentaire: GH Nord - Université Paris Cité, GH Sorbonne Université, GH Henri Mondor, Paris, France
| | - Catherine Chaussain
- Université Paris Cité, Montrouge, France
- AP-HP, Services de médecine bucco-dentaire: GH Nord - Université Paris Cité, GH Sorbonne Université, GH Henri Mondor, Paris, France
- APHP, Centre de reference des maladies rares du phosphate et du calcium (filière OSCAR, ERN BOND), Hôpital Bretonneau, Paris, France
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14
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Novak S, Tanigawa H, Singh V, Root SH, Schmidt TA, Hankenson KD, Kalajzic I. Endothelial to mesenchymal Notch signaling regulates skeletal repair. JCI Insight 2024; 9:e181073. [PMID: 38781018 PMCID: PMC11383173 DOI: 10.1172/jci.insight.181073] [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: 03/12/2024] [Accepted: 05/15/2024] [Indexed: 05/25/2024] Open
Abstract
We present a transcriptomic analysis that provides a better understanding of regulatory mechanisms within the healthy and injured periosteum. The focus of this work is on characterizing early events controlling bone healing during formation of periosteal callus on day 3 after fracture. Building on our previous findings showing that induced Notch1 signaling in osteoprogenitors leads to better healing, we compared samples in which the Notch 1 intracellular domain is overexpressed by periosteal stem/progenitor cells, with control intact and fractured periosteum. Molecular mechanisms and changes in skeletal stem/progenitor cells (SSPCs) and other cell populations within the callus, including hematopoietic lineages, were determined. Notably, Notch ligands were differentially expressed in endothelial and mesenchymal populations, with Dll4 restricted to endothelial cells, whereas Jag1 was expressed by mesenchymal populations. Targeted deletion of Dll4 in endothelial cells using Cdh5CreER resulted in negative effects on early fracture healing, while deletion in SSPCs using α-smooth muscle actin-CreER did not impact bone healing. Translating these observations into a clinically relevant model of bone healing revealed the beneficial effects of delivering Notch ligands alongside the osteogenic inducer, BMP2. These findings provide insights into the regulatory mechanisms within the healthy and injured periosteum, paving the way for novel translational approaches to bone healing.
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Affiliation(s)
- Sanja Novak
- Center for Regenerative Medicine and Skeletal Development, School of Dental Medicine, UConn Health, Farmington, Connecticut, USA
| | - Hitoshi Tanigawa
- Center for Regenerative Medicine and Skeletal Development, School of Dental Medicine, UConn Health, Farmington, Connecticut, USA
| | - Vijender Singh
- Institute for Systems Genomics, Computational Biology Core, UConn, Storrs, Connecticut, USA
| | - Sierra H Root
- Center for Regenerative Medicine and Skeletal Development, School of Dental Medicine, UConn Health, Farmington, Connecticut, USA
| | - Tannin A Schmidt
- Biomedical Engineering Department, School of Dental Medicine, UConn Health, Farmington, Connecticut, USA
| | - Kurt D Hankenson
- Department of Orthopaedic Surgery, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Ivo Kalajzic
- Center for Regenerative Medicine and Skeletal Development, School of Dental Medicine, UConn Health, Farmington, Connecticut, USA
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15
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Al-Mutairi DA, Jarragh AA, Alsabah BH, Wein MN, Mohammed W, Alkharafi L. A homozygous SP7/OSX mutation causes osteogenesis and dentinogenesis imperfecta with craniofacial anomalies. JBMR Plus 2024; 8:ziae026. [PMID: 38562913 PMCID: PMC10984723 DOI: 10.1093/jbmrpl/ziae026] [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: 11/28/2023] [Revised: 02/15/2024] [Accepted: 02/20/2024] [Indexed: 04/04/2024] Open
Abstract
Osteogenesis imperfecta (OI) is a heterogeneous spectrum of hereditary genetic disorders that cause bone fragility, through various quantitative and qualitative defects of type 1 collagen, a triple helix composed of two α1 and one α2 chains encoded by COL1A1 and COL1A2, respectively. The main extra-skeletal manifestations of OI include blue sclerae, opalescent teeth, and hearing impairment. Moreover, multiple genes involved in osteoblast maturation and type 1 collagen biosynthesis are now known to cause recessive forms of OI. In this study a multiplex consanguineous family of two affected males with OI was recruited for genetic screening. To determine the causative, pathogenic variant(s), genomic DNA from two affected family members were analyzed using whole exome sequencing, autozygosity mapping, and then validated with Sanger sequencing. The analysis led to the mapping of a homozygous variant previously reported in SP7/OSX, a gene encoding for Osterix, a transcription factor that activates a repertoire of genes involved in osteoblast and osteocyte differentiation and function. The identified variant (c.946C > T; p.Arg316Cys) in exon 2 of SP7/OSX results in a pathogenic amino acid change in two affected male siblings and develops OI, dentinogenesis imperfecta, and craniofacial anomaly. On the basis of the findings of the present study, SP7/OSX:c. 946C > T is a rare homozygous variant causing OI with extra-skeletal features in inbred Arab populations.
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Affiliation(s)
- Dalal A Al-Mutairi
- Department of Pathology, Faculty of Medicine, Kuwait University, 13110 Kuwait City, Kuwait
| | - Ali A Jarragh
- Department of Surgery, Faculty of Medicine, Kuwait University, 13110 Kuwait City, Kuwait
| | - Basel H Alsabah
- Zain Specialized Hospital for Ear, Nose and Throat, 70030 Kuwait City, Kuwait
| | - Marc N Wein
- Endocrine Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, United States
| | - Wasif Mohammed
- Department of Radiology, Al Sabah Hospital, 13041 Kuwait City, Kuwait
| | - Lateefa Alkharafi
- Cleft and Craniofacial Unit, Farwaniya Specialized Dental Center, Ministry of Health, 13001 Kuwait City, Kuwait
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16
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Heim TE, Hankins ML, Belayneh R, Douglas N, Dinh V, Kovvur M, Boone DN, Ukani V, Bhogal S, Patel V, Moniz TMA, Bailey KM, John I, Schoedel K, Weiss KR, Watters RJ. RNA-sequencing predicts a role of androgen receptor and aldehyde dehydrogenase 1A1 in osteosarcoma lung metastases. Oncogene 2024; 43:1007-1018. [PMID: 38361046 PMCID: PMC10978487 DOI: 10.1038/s41388-024-02957-x] [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: 01/20/2023] [Revised: 09/20/2023] [Accepted: 01/25/2024] [Indexed: 02/17/2024]
Abstract
One-third of pediatric patients with osteosarcoma (OS) develop lung metastases (LM), which is the primary predictor of mortality. While current treatments of patients with localized bone disease have been successful in producing 5-year survival rates of 65-70%, patients with LM experience poor survival rates of only 19-30%. Unacceptably, this situation that has remained unchanged for 30 years. Thus, there is an urgent need to elucidate the mechanisms of metastatic spread in OS and to identify targetable molecular pathways that enable more effective treatments for patients with LM. We aimed to identify OS-specific gene alterations using RNA-sequencing of extremity and LM human tissues. Samples of extremity and LM tumors, including 4 matched sets, were obtained from patients with OS. Our data demonstrate aberrant regulation of the androgen receptor (AR) pathway in LM and predicts aldehyde dehydrogenase 1A1 (ALDH1A1) as a downstream target. Identification of AR pathway upregulation in human LM tissue samples may provide a target for novel therapeutics for patients with LM resistant to conventional chemotherapy.
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Affiliation(s)
- Tanya E Heim
- University of Pittsburgh Department of Orthopaedic Surgery, Pittsburgh, PA, USA.
| | - Margaret L Hankins
- University of Pittsburgh Department of Orthopaedic Surgery, Pittsburgh, PA, USA
| | - Rebekah Belayneh
- University of Pittsburgh Department of Orthopaedic Surgery, Pittsburgh, PA, USA
| | - Nerone Douglas
- University of Pittsburgh Department of Orthopaedic Surgery, Pittsburgh, PA, USA
| | - Vu Dinh
- University of Pittsburgh Department of Orthopaedic Surgery, Pittsburgh, PA, USA
| | - Murali Kovvur
- University of Pittsburgh Department of Orthopaedic Surgery, Pittsburgh, PA, USA
| | - David N Boone
- University of Pittsburgh Department of Biomedical Informatics, Pittsburgh, PA, USA
| | - Vrutika Ukani
- University of Pittsburgh Department of Orthopaedic Surgery, Pittsburgh, PA, USA
| | - Sumail Bhogal
- University of Pittsburgh Department of Orthopaedic Surgery, Pittsburgh, PA, USA
| | - Vaidehi Patel
- University of Pittsburgh Department of Orthopaedic Surgery, Pittsburgh, PA, USA
| | - Taylor M A Moniz
- Columbia University with Trinity College, Dublin, UK
- UPMC Hillman Cancer Center Academy, Pittsburgh, PA, USA
| | - Kelly M Bailey
- University of Pittsburgh School of Medicine, Department of Pediatrics, Pittsburgh, PA, USA
| | - Ivy John
- University of Pittsburgh Department of Pathology, Pittsburgh, PA, USA
| | - Karen Schoedel
- University of Pittsburgh Department of Pathology, Pittsburgh, PA, USA
| | - Kurt R Weiss
- University of Pittsburgh Department of Orthopaedic Surgery, Pittsburgh, PA, USA
| | - Rebecca J Watters
- University of Pittsburgh Department of Orthopaedic Surgery, Pittsburgh, PA, USA
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17
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Torres HM, Hinojosa L, VanCleave AM, Rodezno T, Westendorf JJ, Tao J. Hdac1 and Hdac2 positively regulate Notch1 gain-of-function pathogenic signaling in committed osteoblasts of male mice. Birth Defects Res 2024; 116:e2266. [PMID: 37921375 PMCID: PMC10842522 DOI: 10.1002/bdr2.2266] [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: 07/18/2023] [Revised: 10/18/2023] [Accepted: 10/19/2023] [Indexed: 11/04/2023]
Abstract
BACKGROUND Skeletal development requires precise extrinsic and intrinsic signals to regulate processes that form and maintain bone and cartilage. Notch1 is a highly conserved signaling receptor that regulates cell fate decisions by controlling the duration of transcriptional bursts. Epigenetic molecular events reversibly modify DNA and histone tails by influencing the spatial organization of chromatin and can fine-tune the outcome of a Notch1 transcriptional response. Histone deacetylase 1 and 2 (HDAC1 and HDAC2) are chromatin modifying enzymes that mediate osteoblast differentiation. While an HDAC1-Notch interaction has been studied in vitro and in Drosophila, its role in mammalian skeletal development and disorders is unclear. Osteosclerosis is a bone disorder with an abnormal increase in the number of osteoblasts and excessive bone formation. METHODS Here, we tested whether Hdac1/2 contribute to the pathogenesis of osteosclerosis in a murine model of the disease owing to conditionally cre-activated expression of the Notch1 intracellular domain in immature osteoblasts. RESULTS Importantly, selective homozygous deletions of Hdac1/2 in osteoblasts partially alleviate osteosclerotic phenotypes (Col2.3kb-Cre; TGRosaN1ICD/+ ; Hdac1flox/flox ; Hdac2flox/flox ) with a 40% decrease in bone volume and a 22% decrease in trabecular thickness in 4 weeks old when compared to male mice with heterozygous deletions of Hdac1/2 (Col2.3 kb-Cre; TGRosaN1ICD/+ ; Hdac1flox/+ ; Hdac2flox/+ ). Osteoblast-specific deletion of Hdac1/2 in male and female mice results in no overt bone phenotype in the absence of the Notch1 gain-of-function (GOF) allele. CONCLUSIONS These results provide evidence that Hdac1/2 contribute to Notch1 pathogenic signaling in the mammalian skeleton. Our study on epigenetic regulation of Notch1 GOF-induced osteosclerosis may facilitate further mechanistic studies of skeletal birth defects caused by Notch-related GOF mutations in human patients, such as Adams-Oliver disease, congenital heart disease, and lateral meningocele syndrome.
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Affiliation(s)
- Haydee M. Torres
- Cancer Biology and Immunotherapies Group, Sanford Research, Sioux Falls, South Dakota, USA
- Department of Chemistry and Biochemistry, South Dakota State University, Brookings, South Dakota, USA
- Department of Orthopedic Surgery, Mayo Clinic, Rochester, Minnesota, USA
| | - Leetoria Hinojosa
- Cancer Biology and Immunotherapies Group, Sanford Research, Sioux Falls, South Dakota, USA
| | - Ashley M. VanCleave
- Cancer Biology and Immunotherapies Group, Sanford Research, Sioux Falls, South Dakota, USA
| | - Tania Rodezno
- Cancer Biology and Immunotherapies Group, Sanford Research, Sioux Falls, South Dakota, USA
| | - Jennifer J. Westendorf
- Department of Orthopedic Surgery, Mayo Clinic, Rochester, Minnesota, USA
- Department of Biochemistry & Molecular Biology, Mayo Clinic, Rochester, Minnesota, USA
| | - Jianning Tao
- Cancer Biology and Immunotherapies Group, Sanford Research, Sioux Falls, South Dakota, USA
- Department of Chemistry and Biochemistry, South Dakota State University, Brookings, South Dakota, USA
- Department of Pediatrics and Biomedical Engineering at the University of South Dakota, Sioux Falls, South Dakota, USA
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18
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Luján-Amoraga L, Delgado-Martín B, Lourenço-Marques C, Gavaia PJ, Bravo J, Bandarra NM, Dominguez D, Izquierdo MS, Pousão-Ferreira P, Ribeiro L. Exploring Omega-3's Impact on the Expression of Bone-Related Genes in Meagre ( Argyrosomus regius). Biomolecules 2023; 14:56. [PMID: 38254657 PMCID: PMC10813611 DOI: 10.3390/biom14010056] [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: 10/31/2023] [Revised: 12/20/2023] [Accepted: 12/22/2023] [Indexed: 01/24/2024] Open
Abstract
Dietary supplementation with Omega-3 fatty acids seems to promote skeletal health. Therefore, their consumption at imbalanced or excessive levels has offered less beneficial or even prejudicial effects. Fish produced in aquaculture regimes are prone to develop abnormal skeletons. Although larval cultures are usually fed with diets supplemented with Omega-3 Long Chain Polyunsaturated fatty acids (LC-PUFAs), the lack of knowledge about the optimal requirements for fatty acids or about their impact on mechanisms that regulate skeletal development has impeded the design of diets that could improve bone formation during larval stages when the majority of skeletal anomalies appear. In this study, Argyrosomus regius larvae were fed different levels of Omega-3s (2.6% and 3.6% DW on diet) compared to a commercial diet. At 28 days after hatching (DAH), their transcriptomes were analyzed to study the modulation exerted in gene expression dynamics during larval development and identify impacted genes that can contribute to skeletal formation. Mainly, both levels of supplementation modulated bone-cell proliferation, the synthesis of bone components such as the extracellular matrix, and molecules involved in the interaction and signaling between bone components or in important cellular processes. The 2.6% level impacted several genes related to cartilage development, denoting a special impact on endochondral ossification, delaying this process. However, the 3.6% level seemed to accelerate this process by enhancing skeletal development. These results offered important insights into the impact of dietary Omega-3 LC-PUFAs on genes involved in the main molecular mechanism and cellular processes involved in skeletal development.
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Affiliation(s)
- Leticia Luján-Amoraga
- Aquaculture Research Station (EPPO), Portuguese Institute for the Ocean and Atmosphere (IPMA), 8700-194 Olhão, Portugal; (L.L.-A.); (C.L.-M.); (P.P.-F.)
| | - Belén Delgado-Martín
- Department of Microbiology and Crop Protection, Institute of Subtropical and Mediterranean Horticulture (IHSM-UMA-CSIC), 29010 Malaga, Spain;
| | - Cátia Lourenço-Marques
- Aquaculture Research Station (EPPO), Portuguese Institute for the Ocean and Atmosphere (IPMA), 8700-194 Olhão, Portugal; (L.L.-A.); (C.L.-M.); (P.P.-F.)
- Collaborative Laboratory on Sustainable and Smart Aquaculture (S2AQUACOLAB) Av. Parque Natural da Ria Formosa s/n, 8700-194 Olhão, Portugal
| | - Paulo J. Gavaia
- Centre of Marine Sciences (CCMAR), University of Algarve (UALG), 8005-139 Faro, Portugal;
| | - Jimena Bravo
- Aquaculture Research Group (GIA), University of Las Palmas de Gran Canaria (ULPGC) Crta. Taliarte s/n, 35214 Telde, Spain; (J.B.); (D.D.); (M.S.I.)
| | - Narcisa M. Bandarra
- Division of Aquaculture, Upgrading, and Bioprospection (DivAV), Portuguese Institute for the Sea and Atmosphere (IPMA, IP), Rua Alfredo Magalhães Ramalho, 7, 1495-006 Lisbon, Portugal;
- CIIMAR, Interdisciplinary Centre of Marine and Environmental Research, University of Porto, Rua dos Bragas 289, 4050-123 Porto, Portugal
| | - David Dominguez
- Aquaculture Research Group (GIA), University of Las Palmas de Gran Canaria (ULPGC) Crta. Taliarte s/n, 35214 Telde, Spain; (J.B.); (D.D.); (M.S.I.)
| | - Marisol S. Izquierdo
- Aquaculture Research Group (GIA), University of Las Palmas de Gran Canaria (ULPGC) Crta. Taliarte s/n, 35214 Telde, Spain; (J.B.); (D.D.); (M.S.I.)
| | - Pedro Pousão-Ferreira
- Aquaculture Research Station (EPPO), Portuguese Institute for the Ocean and Atmosphere (IPMA), 8700-194 Olhão, Portugal; (L.L.-A.); (C.L.-M.); (P.P.-F.)
- Collaborative Laboratory on Sustainable and Smart Aquaculture (S2AQUACOLAB) Av. Parque Natural da Ria Formosa s/n, 8700-194 Olhão, Portugal
| | - Laura Ribeiro
- Aquaculture Research Station (EPPO), Portuguese Institute for the Ocean and Atmosphere (IPMA), 8700-194 Olhão, Portugal; (L.L.-A.); (C.L.-M.); (P.P.-F.)
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Liu G, Wei J, Xiao W, Xie W, Ru Q, Chen L, Wu Y, Mobasheri A, Li Y. Insights into the Notch signaling pathway in degenerative musculoskeletal disorders: Mechanisms and perspectives. Biomed Pharmacother 2023; 169:115884. [PMID: 37981460 DOI: 10.1016/j.biopha.2023.115884] [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: 09/24/2023] [Revised: 11/08/2023] [Accepted: 11/13/2023] [Indexed: 11/21/2023] Open
Abstract
Degenerative musculoskeletal disorders are a group of age-related diseases of the locomotive system that severely affects the patient's ability to work and cause adverse sequalae such as fractures and even death. The incidence and prevalence of degenerative musculoskeletal disorders is rising owing to the aging of the world's population. The Notch signaling pathway, which is expressed in almost all organ systems, extensively regulates cell proliferation and differentiation as well as cellular fate. Notch signaling shows increased activity in degenerative musculoskeletal disorders and retards the progression of degeneration to some extent. The review focuses on four major degenerative musculoskeletal disorders (osteoarthritis, intervertebral disc degeneration, osteoporosis, and sarcopenia) and summarizes the pathophysiological functions of Notch signaling in these disorders, especially its role in stem/progenitor cells in each disorder. Finally, a conclusion will be presented to explore the research and application of the perspectives on Notch signaling in degenerative musculoskeletal disorders.
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Affiliation(s)
- Gaoming Liu
- Department of Orthopedics, Xiangya Hospital, Central South University, Changsha 410011, China
| | - Jun Wei
- Department of Clinical Medical School, Xinjiang Medical University, Urumqi 830054, China
| | - Wenfeng Xiao
- Department of Orthopedics, Xiangya Hospital, Central South University, Changsha 410011, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410011, China
| | - Wenqing Xie
- Department of Orthopedics, Xiangya Hospital, Central South University, Changsha 410011, China
| | - Qin Ru
- Department of Health and Physical Education, Jianghan University, Wuhan 430056, China
| | - Lin Chen
- Department of Health and Physical Education, Jianghan University, Wuhan 430056, China
| | - Yuxiang Wu
- Department of Health and Physical Education, Jianghan University, Wuhan 430056, China.
| | - Ali Mobasheri
- Research Unit of Medical Imaging, Physics and Technology, Faculty of Medicine, University of Oulu, Oulu, Finland; Department of Regenerative Medicine, State Research Institute Centre for Innovative Medicine, Vilnius, Lithuania; Department of Orthopedics, University Medical Center Utrecht, Utrecht, the Netherlands; Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht, the Netherlands; Department of Joint Surgery, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China; World Health Organization Collaborating Center for Public Health Aspects of Musculoskeletal Health and Aging, Université de Liège, Liège, Belgium.
| | - Yusheng Li
- Department of Orthopedics, Xiangya Hospital, Central South University, Changsha 410011, China; Department of Clinical Medical School, Xinjiang Medical University, Urumqi 830054, China.
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20
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Tomasoni C, Arsuffi C, Donsante S, Corsi A, Riminucci M, Biondi A, Pievani A, Serafini M. AML alters bone marrow stromal cell osteogenic commitment via Notch signaling. Front Immunol 2023; 14:1320497. [PMID: 38111584 PMCID: PMC10725948 DOI: 10.3389/fimmu.2023.1320497] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2023] [Accepted: 11/20/2023] [Indexed: 12/20/2023] Open
Abstract
Introduction Acute myeloid leukemia (AML) is a highly heterogeneous malignancy caused by various genetic alterations and characterized by the accumulation of immature myeloid blasts in the bone marrow (BM). This abnormal growth of AML cells disrupts normal hematopoiesis and alters the BM microenvironment components, establishing a niche supportive of leukemogenesis. Bone marrow stromal cells (BMSCs) play a pivotal role in giving rise to essential elements of the BM niche, including adipocytes and osteogenic cells. Animal models have shown that the BM microenvironment is significantly remodeled by AML cells, which skew BMSCs toward an ineffective osteogenic differentiation with an accumulation of osteoprogenitors. However, little is known about the mechanisms by which AML cells affect osteogenesis. Methods We studied the effect of AML cells on the osteogenic commitment of normal BMSCs, using a 2D co-culture system. Results We found that AML cell lines and primary blasts, but not normal hematopoietic CD34+ cells, induced in BMSCs an ineffective osteogenic commitment, with an increase of the early-osteogenic marker tissue non-specific alkaline phosphatase (TNAP) in the absence of the late-osteogenic gene up-regulation. Moreover, the direct interaction of AML cells and BMSCs was indispensable in influencing osteogenic differentiation. Mechanistic studies identified a role for AML-mediated Notch activation in BMSCs contributing to their ineffective osteogenic commitment. Inhibition of Notch using a γ-secretase inhibitor strongly influenced Notch signaling in BMSCs and abrogated the AML-induced TNAP up-regulation. Discussion Together, our data support the hypothesis that AML infiltration produces a leukemia-supportive pre-osteoblast-rich niche in the BM, which can be partially ascribed to AML-induced activation of Notch signaling in BMSCs.
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Affiliation(s)
- Chiara Tomasoni
- Tettamanti Center, Fondazione Istituto Ricovero e Cura a Carattere Scientifico (IRCCS) San Gerardo dei Tintori, Monza, Italy
| | - Corinne Arsuffi
- Tettamanti Center, Fondazione Istituto Ricovero e Cura a Carattere Scientifico (IRCCS) San Gerardo dei Tintori, Monza, Italy
| | - Samantha Donsante
- Tettamanti Center, Fondazione Istituto Ricovero e Cura a Carattere Scientifico (IRCCS) San Gerardo dei Tintori, Monza, Italy
- Department of Molecular Medicine, Sapienza University, Rome, Italy
| | - Alessandro Corsi
- Department of Molecular Medicine, Sapienza University, Rome, Italy
| | - Mara Riminucci
- Department of Molecular Medicine, Sapienza University, Rome, Italy
| | - Andrea Biondi
- Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
- Pediatrics, Fondazione Istituto Ricovero e Cura a Carattere Scientifico (IRCCS) San Gerardo dei Tintori, Monza, Italy
| | - Alice Pievani
- Tettamanti Center, Fondazione Istituto Ricovero e Cura a Carattere Scientifico (IRCCS) San Gerardo dei Tintori, Monza, Italy
| | - Marta Serafini
- Tettamanti Center, Fondazione Istituto Ricovero e Cura a Carattere Scientifico (IRCCS) San Gerardo dei Tintori, Monza, Italy
- Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
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21
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Canalis E, Yu J, Singh V, Mocarska M, Schilling L. NOTCH2 sensitizes the chondrocyte to the inflammatory response of tumor necrosis factor α. J Biol Chem 2023; 299:105372. [PMID: 37865314 PMCID: PMC10692730 DOI: 10.1016/j.jbc.2023.105372] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Revised: 10/06/2023] [Accepted: 10/15/2023] [Indexed: 10/23/2023] Open
Abstract
Notch regulates the immune and inflammatory response and has been associated with the pathogenesis of osteoarthritis in humans and preclinical models of the disease. Notch2tm1.1Ecan mice harbor a NOTCH2 gain-of-function and are sensitized to osteoarthritis, but the mechanisms have not been explored. We examined the effects of tumor necrosis factor α (TNFα) in chondrocytes from Notch2tm1.1Ecan mice and found that NOTCH2 enhanced the effect of TNFα on Il6 and Il1b expression. Similar results were obtained in cells from a conditional model of NOTCH2 gain-of-function, Notch22.1Ecan mice, and following the expression of the NOTCH2 intracellular domain in vitro. Recombination signal-binding protein for immunoglobulin Kappa J region partners with the NOTCH2 intracellular domain to activate transcription; in the absence of Notch signaling it inhibits transcription, and Rbpj inactivation in chondrocytes resulted in Il6 induction. Although TNFα induced IL6 to a greater extent in the context of NOTCH2 activation, there was a concomitant inhibition of Notch target genes Hes1, Hey1, Hey2, and Heyl. Electrophoretic mobility shift assay demonstrated displacement of recombination signal-binding protein for immunoglobulin Kappa J region from DNA binding sites by TNFα explaining the increased Il6 expression and the concomitant decrease in Notch target genes. NOTCH2 enhanced the effect of TNFα on NF-κB signaling, and RNA-Seq revealed increased expression of pathways associated with inflammation and the phagosome in NOTCH2 overexpressing cells in the absence and presence of TNFα. Collectively, NOTCH2 has important interactions with TNFα resulting in the enhanced expression of Il6 and inflammatory pathways in chondrocytes.
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Affiliation(s)
- Ernesto Canalis
- Department of Orthopaedic Surgery, UConn Health, Farmington, Connecticut, USA; Department of Medicine, UConn Health, Farmington, Connecticut, USA; UConn Musculoskeletal Institute, UConn Health, Farmington, Connecticut, USA.
| | - Jungeun Yu
- Department of Orthopaedic Surgery, UConn Health, Farmington, Connecticut, USA; UConn Musculoskeletal Institute, UConn Health, Farmington, Connecticut, USA
| | - Vijender Singh
- Computational Biology Core, Institute for System Genomics, UConn, Storrs, Connecticut, USA
| | - Magda Mocarska
- UConn Musculoskeletal Institute, UConn Health, Farmington, Connecticut, USA
| | - Lauren Schilling
- UConn Musculoskeletal Institute, UConn Health, Farmington, Connecticut, USA
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22
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Leser JM, Torre OM, Gould NR, Guo Q, Buck HV, Kodama J, Otsuru S, Stains JP. Osteoblast-lineage calcium/calmodulin-dependent kinase 2 delta and gamma regulates bone mass and quality. Proc Natl Acad Sci U S A 2023; 120:e2304492120. [PMID: 37976259 PMCID: PMC10666124 DOI: 10.1073/pnas.2304492120] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Accepted: 09/30/2023] [Indexed: 11/19/2023] Open
Abstract
Bone regulates its mass and quality in response to diverse mechanical, hormonal, and local signals. The bone anabolic or catabolic responses to these signals are often received by osteocytes, which then coordinate the activity of osteoblasts and osteoclasts on bone surfaces. We previously established that calcium/calmodulin-dependent kinase 2 (CaMKII) is required for osteocytes to respond to some bone anabolic cues in vitro. However, a role for CaMKII in bone physiology in vivo is largely undescribed. Here, we show that conditional codeletion of the most abundant isoforms of CaMKII (delta and gamma) in mature osteoblasts and osteocytes [Ocn-cre:Camk2d/Camk2g double-knockout (dCKO)] caused severe osteopenia in both cortical and trabecular compartments by 8 wk of age. In addition to having less bone mass, dCKO bones are of worse quality, with significant deficits in mechanical properties, and a propensity to fracture. This striking skeletal phenotype is multifactorial, including diminished osteoblast activity, increased osteoclast activity, and altered phosphate homeostasis both systemically and locally. These dCKO mice exhibited decreased circulating phosphate (hypophosphatemia) and increased expression of the phosphate-regulating hormone fibroblast growth factor 23. Additionally, dCKO mice expressed less bone-derived tissue nonspecific alkaline phosphatase protein than control mice. Consistent with altered phosphate homeostasis, we observed that dCKO bones were hypo-mineralized with prominent osteoid seams, analogous to the phenotypes of mice with hypophosphatemia. Altogether, these data reveal a fundamental role for osteocyte CaMKIIδ and CaMKIIγ in the maintenance of bone mass and bone quality and link osteoblast/osteocyte CaMKII to phosphate homeostasis.
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Affiliation(s)
- Jenna M. Leser
- Department of Othopaedics, University of Maryland School of Medicine, Baltimore, MD21201
| | - Olivia M. Torre
- Department of Othopaedics, University of Maryland School of Medicine, Baltimore, MD21201
| | - Nicole R. Gould
- Department of Othopaedics, University of Maryland School of Medicine, Baltimore, MD21201
| | - Qiaoyue Guo
- Department of Othopaedics, University of Maryland School of Medicine, Baltimore, MD21201
| | - Heather V. Buck
- Department of Othopaedics, University of Maryland School of Medicine, Baltimore, MD21201
| | - Joe Kodama
- Department of Othopaedics, University of Maryland School of Medicine, Baltimore, MD21201
| | - Satoru Otsuru
- Department of Othopaedics, University of Maryland School of Medicine, Baltimore, MD21201
| | - Joseph P. Stains
- Department of Othopaedics, University of Maryland School of Medicine, Baltimore, MD21201
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23
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Remark LH, Leclerc K, Ramsukh M, Lin Z, Lee S, Dharmalingam B, Gillinov L, Nayak VV, El Parente P, Sambon M, Atria PJ, Ali MAE, Witek L, Castillo AB, Park CY, Adams RH, Tsirigos A, Morgani SM, Leucht P. Loss of Notch signaling in skeletal stem cells enhances bone formation with aging. Bone Res 2023; 11:50. [PMID: 37752132 PMCID: PMC10522593 DOI: 10.1038/s41413-023-00283-8] [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: 01/04/2023] [Revised: 07/06/2023] [Accepted: 07/19/2023] [Indexed: 09/28/2023] Open
Abstract
Skeletal stem and progenitor cells (SSPCs) perform bone maintenance and repair. With age, they produce fewer osteoblasts and more adipocytes leading to a loss of skeletal integrity. The molecular mechanisms that underlie this detrimental transformation are largely unknown. Single-cell RNA sequencing revealed that Notch signaling becomes elevated in SSPCs during aging. To examine the role of increased Notch activity, we deleted Nicastrin, an essential Notch pathway component, in SSPCs in vivo. Middle-aged conditional knockout mice displayed elevated SSPC osteo-lineage gene expression, increased trabecular bone mass, reduced bone marrow adiposity, and enhanced bone repair. Thus, Notch regulates SSPC cell fate decisions, and moderating Notch signaling ameliorates the skeletal aging phenotype, increasing bone mass even beyond that of young mice. Finally, we identified the transcription factor Ebf3 as a downstream mediator of Notch signaling in SSPCs that is dysregulated with aging, highlighting it as a promising therapeutic target to rejuvenate the aged skeleton.
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Affiliation(s)
- Lindsey H Remark
- Department of Orthopaedic Surgery, NYU Robert I. Grossman School of Medicine, New York, NY, USA
| | - Kevin Leclerc
- Department of Orthopaedic Surgery, NYU Robert I. Grossman School of Medicine, New York, NY, USA
| | - Malissa Ramsukh
- Department of Orthopaedic Surgery, NYU Robert I. Grossman School of Medicine, New York, NY, USA
| | - Ziyan Lin
- Applied Bioinformatics Laboratories, NYU Grossman School of Medicine, New York, NY, USA
| | - Sooyeon Lee
- Department of Orthopaedic Surgery, NYU Robert I. Grossman School of Medicine, New York, NY, USA
- Institute of Comparative Molecular Endocrinology, Ulm University, Ulm, Germany
| | - Backialakshmi Dharmalingam
- Max Planck Institute for Molecular Biomedicine, Department of Tissue Morphogenesis, and University of Münster, Faculty of Medicine, D-48149, Münster, Germany
| | - Lauren Gillinov
- Department of Orthopaedic Surgery, NYU Robert I. Grossman School of Medicine, New York, NY, USA
| | - Vasudev V Nayak
- Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Paulo El Parente
- Department of Orthopaedic Surgery, NYU Robert I. Grossman School of Medicine, New York, NY, USA
| | - Margaux Sambon
- Department of Orthopaedic Surgery, NYU Robert I. Grossman School of Medicine, New York, NY, USA
| | - Pablo J Atria
- Department of Orthopaedic Surgery, NYU Robert I. Grossman School of Medicine, New York, NY, USA
| | - Mohamed A E Ali
- Department of Pathology, NYU Robert I. Grossman School of Medicine, New York, NY, USA
| | - Lukasz Witek
- Biomaterials Division, New York University College of Dentistry, New York, NY, USA
- Hansjörg Wyss Department of Plastic Surgery, NYU Grossman School of Medicine, New York University, New York, NY, USA
- Department of Biomedical Engineering, Tandon School of Engineering, New York University, Brooklyn, NY, USA
| | - Alesha B Castillo
- Department of Orthopaedic Surgery, NYU Robert I. Grossman School of Medicine, New York, NY, USA
| | - Christopher Y Park
- Department of Pathology, NYU Robert I. Grossman School of Medicine, New York, NY, USA
| | - Ralf H Adams
- Max Planck Institute for Molecular Biomedicine, Department of Tissue Morphogenesis, and University of Münster, Faculty of Medicine, D-48149, Münster, Germany
| | - Aristotelis Tsirigos
- Applied Bioinformatics Laboratories, NYU Grossman School of Medicine, New York, NY, USA
| | - Sophie M Morgani
- Department of Orthopaedic Surgery, NYU Robert I. Grossman School of Medicine, New York, NY, USA
| | - Philipp Leucht
- Department of Orthopaedic Surgery, NYU Robert I. Grossman School of Medicine, New York, NY, USA.
- Department of Cell Biology, NYU Robert I. Grossman School of Medicine, New York, NY, USA.
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24
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Diaz C, Thankam FG, Agrawal DK. Karyopherins in the Remodeling of Extracellular Matrix: Implications in Tendon Injury. JOURNAL OF ORTHOPAEDICS AND SPORTS MEDICINE 2023; 5:357-374. [PMID: 37829147 PMCID: PMC10569131 DOI: 10.26502/josm.511500122] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/14/2023]
Abstract
Rotator Cuff Tendinopathies (RCT) are debilitating conditions characterized by alterations in the extracellular matrix (ECM) of the shoulder tendon, resulting in pain, discomfort, and functional limitations. Specific mediators, including HIF-1α, TGF-β, MMP-9 and others have been implicated in the morphological changes observed in the tendon ECM. These mediators rely on karyopherins, a family of nuclear proteins involved in nucleo-cytoplasmic transport; however, the role of karyopherins in RCT remains understudied despite their potential role in nuclear transport mechanisms. Also, the understanding regarding the precise contributions of karyopherins in RCT holds great promise for deciphering the underlying pathophysiological mechanisms of the disease and potentially fostering the development of targeted therapeutic strategies. This article critically discusses the implications, possibilities, and perspectives of karyopherins in the pathophysiology of RCT.
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Affiliation(s)
- Connor Diaz
- University of Missouri School of Medicine, Springfield Clinical Campus, Springfield, MO 65807, USA
| | - Finosh G Thankam
- Department of Translational Research, Western University of Health Sciences, Pomona, California 91766, USA
| | - Devendra K Agrawal
- Department of Translational Research, Western University of Health Sciences, Pomona, California 91766, USA
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25
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Kaimari S, Kamalakar A, Goudy SL. Biomedical engineering approaches for the delivery of JAGGED1 as a potential tissue regenerative therapy. Front Bioeng Biotechnol 2023; 11:1217211. [PMID: 37781534 PMCID: PMC10534981 DOI: 10.3389/fbioe.2023.1217211] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Accepted: 08/31/2023] [Indexed: 10/03/2023] Open
Abstract
JAG1 is a ligand that activates the NOTCH signaling pathway which plays a crucial role in determining cell fate behavior through cell-to-cell signaling. JAG1-NOTCH signaling is required for mesenchymal stem cell (MSC) differentiation into cardiomyocytes and cranial neural crest (CNC) cells differentiation into osteoblasts, making it a regenerative candidate for clinical therapy to treat craniofacial bone loss and myocardial infarction. However, delivery of soluble JAG1 has been found to inhibit NOTCH signaling due to the requirement of JAG1 presentation in a bound form. For JAG1-NOTCH signaling to occur, JAG1 must be immobilized within a scaffold and the correct orientation between the NOTCH receptor and JAG1 must be achieved. The lack of clinically translatable JAG1 delivery methods has driven the exploration of alternative immobilization approaches. This review discusses the role of JAG1 in disease, the clinical role of JAG1 as a treatment, and summarizes current approaches for JAG1 delivery. An in-depth review was conducted on literature that used both in vivo and in vitro delivery models and observed the canonical versus non-canonical NOTCH pathway activated by JAG1. Studies were then compared and evaluated based on delivery success, functional outcomes, and translatability. Delivering JAG1 to harness its ability to control cell fate has the potential to serve as a therapeutic for many diseases.
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Affiliation(s)
- Sundus Kaimari
- Department of Pediatric Otolaryngology, Emory University, Atlanta, GA, United States
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA, United States
| | - Archana Kamalakar
- Department of Pediatric Otolaryngology, Emory University, Atlanta, GA, United States
| | - Steven L. Goudy
- Department of Pediatric Otolaryngology, Emory University, Atlanta, GA, United States
- Department of Pediatric Otolaryngology, Children’s Healthcare of Atlanta, Atlanta, GA, United States
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26
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Kidwai FK, Canalis E, Robey PG. Induced pluripotent stem cell technology in bone biology. Bone 2023; 172:116760. [PMID: 37028583 PMCID: PMC10228209 DOI: 10.1016/j.bone.2023.116760] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2023] [Revised: 03/31/2023] [Accepted: 04/04/2023] [Indexed: 04/09/2023]
Abstract
Technologies on the development and differentiation of human induced pluripotent stem cells (hiPSCs) are rapidly improving, and have been applied to create cell types relevant to the bone field. Differentiation protocols to form bona fide bone-forming cells from iPSCs are available, and can be used to probe details of differentiation and function in depth. When applied to iPSCs bearing disease-causing mutations, the pathogenetic mechanisms of diseases of the skeleton can be elucidated, along with the development of novel therapeutics. These cells can also be used for development of cell therapies for cell and tissue replacement.
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Affiliation(s)
- Fahad K Kidwai
- Skeletal Biology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892, United States of America
| | - Ernesto Canalis
- Center for Skeletal Research, Orthopedic Surgery and Medicine, UConn Musculoskeletal Institute, UConn Health, Farmington, CT 06030-4037, United States of America
| | - Pamela G Robey
- Skeletal Biology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892, United States of America.
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27
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Vimalraj S, Sekaran S. RUNX Family as a Promising Biomarker and a Therapeutic Target in Bone Cancers: A Review on Its Molecular Mechanism(s) behind Tumorigenesis. Cancers (Basel) 2023; 15:3247. [PMID: 37370857 DOI: 10.3390/cancers15123247] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Revised: 06/10/2023] [Accepted: 06/13/2023] [Indexed: 06/29/2023] Open
Abstract
The transcription factor runt-related protein (RUNX) family is the major transcription factor responsible for the formation of osteoblasts from bone marrow mesenchymal stem cells, which are involved in bone formation. Accumulating evidence implicates the RUNX family for its role in tumor biology and cancer progression. The RUNX family has been linked to osteosarcoma via its regulation of many tumorigenicity-related factors. In the regulatory network of cancers, with numerous upstream signaling pathways and its potential target molecules downstream, RUNX is a vital molecule. Hence, a pressing need exists to understand the precise process underpinning the occurrence and prognosis of several malignant tumors. Until recently, RUNX has been regarded as one of the therapeutic targets for bone cancer. Therefore, in this review, we have provided insights into various molecular mechanisms behind the tumorigenic role of RUNX in various important cancers. RUNX is anticipated to grow into a novel therapeutic target with the in-depth study of RUNX family-related regulatory processes, aid in the creation of new medications, and enhance clinical efficacy.
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Affiliation(s)
- Selvaraj Vimalraj
- Department of Prosthodontics, Saveetha Dental College and Hospital, Saveetha Institute of Medical and Technical Sciences (SIMATS), Saveetha University, Chennai 600077, Tamil Nadu, India
| | - Saravanan Sekaran
- Department of Prosthodontics, Saveetha Dental College and Hospital, Saveetha Institute of Medical and Technical Sciences (SIMATS), Saveetha University, Chennai 600077, Tamil Nadu, India
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28
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Sarkaria SM, Zhou J, Bao S, Zhao W, Fang Y, Que J, Bhagat G, Zhang C, Ding L. Systematic dissection of coordinated stromal remodeling identifies Sox10 + glial cells as a therapeutic target in myelofibrosis. Cell Stem Cell 2023; 30:832-850.e6. [PMID: 37267917 PMCID: PMC10240254 DOI: 10.1016/j.stem.2023.05.002] [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: 03/22/2022] [Revised: 10/24/2022] [Accepted: 05/02/2023] [Indexed: 06/04/2023]
Abstract
Remodeling of the tissue niche is often evident in diseases, yet, the stromal alterations and their contribution to pathogenesis are poorly characterized. Bone marrow fibrosis is a maladaptive feature of primary myelofibrosis (PMF). We performed lineage tracing and found that most collagen-expressing myofibroblasts were derived from leptin-receptor-positive (LepR+) mesenchymal cells, whereas a minority were from Gli1-lineage cells. Deletion of Gli1 did not impact PMF. Unbiased single-cell RNA sequencing (scRNA-seq) confirmed that virtually all myofibroblasts originated from LepR-lineage cells, with reduced expression of hematopoietic niche factors and increased expression of fibrogenic factors. Concurrently, endothelial cells upregulated arteriolar-signature genes. Pericytes and Sox10+ glial cells expanded drastically with heightened cell-cell signaling, suggesting important functional roles in PMF. Chemical or genetic ablation of bone marrow glial cells ameliorated fibrosis and improved other pathology in PMF. Thus, PMF involves complex remodeling of the bone marrow microenvironment, and glial cells represent a promising therapeutic target.
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Affiliation(s)
- Shawn M Sarkaria
- Columbia Stem Cell Initiative, Department of Rehabilitation and Regenerative Medicine, Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, NY 10032, USA; Division of Hematology and Medical Oncology, Department of Medicine, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Junsong Zhou
- Columbia Stem Cell Initiative, Department of Rehabilitation and Regenerative Medicine, Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Suying Bao
- Department of Systems Biology, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Wenqi Zhao
- Columbia Stem Cell Initiative, Department of Rehabilitation and Regenerative Medicine, Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Yinshan Fang
- Division of Digestive and Liver Diseases, Columbia Center for Human Development, Department of Medicine, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Jianwen Que
- Division of Digestive and Liver Diseases, Columbia Center for Human Development, Department of Medicine, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Govind Bhagat
- Division of Hematopathology, Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Chaolin Zhang
- Department of Systems Biology, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Lei Ding
- Columbia Stem Cell Initiative, Department of Rehabilitation and Regenerative Medicine, Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, NY 10032, USA.
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Abstract
PURPOSE OF REVIEW Aortic valve disease is a leading global cause of morbidity and mortality, posing an increasing burden on society. Advances in next-generation technologies and disease models over the last decade have further delineated the genetic and molecular factors that might be exploited in development of therapeutics for affected patients. This review describes several advances in the molecular and genetic understanding of AVD, focusing on bicuspid aortic valve (BAV) and calcific aortic valve disease (CAVD). RECENT FINDINGS Genomic studies have identified a myriad of genes implicated in the development of BAV, including NOTCH1 , SMAD6 and ADAMTS19 , along with members of the GATA and ROBO gene families. Similarly, several genes associated with the initiation and progression of CAVD, including NOTCH1 , LPA , PALMD , IL6 and FADS1/2 , serve as the launching point for emerging clinical trials. SUMMARY These new insights into the genetic contributors of AVD have offered new avenues for translational disease investigation, bridging molecular discoveries to emergent pharmacotherapeutic options. Future studies aimed at uncovering new genetic associations and further defining implicated molecular pathways are fuelling the new wave of drug discovery.
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Affiliation(s)
- Ruth L. Ackah
- Center for Cardiovascular Research, Abigail Wexner Research Institute, Nationwide Children’s Hospital, Columbus, Ohio, USA
- The Heart Center, Nationwide Children’s Hospital, Columbus, Ohio, USA
- Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH
| | - Jun Yasuhara
- Center for Cardiovascular Research, Abigail Wexner Research Institute, Nationwide Children’s Hospital, Columbus, Ohio, USA
- The Heart Center, Nationwide Children’s Hospital, Columbus, Ohio, USA
| | - Vidu Garg
- Center for Cardiovascular Research, Abigail Wexner Research Institute, Nationwide Children’s Hospital, Columbus, Ohio, USA
- The Heart Center, Nationwide Children’s Hospital, Columbus, Ohio, USA
- Department of Pediatrics, The Ohio State University, Columbus, Ohio, USA
- Department of Molecular Genetics, The Ohio State University, Columbus, Ohio, USA
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Sivaraman L, Sanderson T. Gamma secretase inhibition: Effects on fertility and embryo-fetal development in rats. Toxicol Appl Pharmacol 2023; 469:116512. [PMID: 37030625 DOI: 10.1016/j.taap.2023.116512] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Revised: 03/21/2023] [Accepted: 04/04/2023] [Indexed: 04/08/2023]
Abstract
Avagacestat inhibits γ-secretase, a protease that cleaves the amyloid precursor protein (APP) to produce amyloid beta (Aβ). Aβ plaques, a predominant lesion in Alzheimer's patient's brain, is considered a mechanism driving neurodegeneration. As part of the nonclinical reproductive safety assessment, avagacestat effects on fertility and early embryonic development and embryo-fetal development were evaluated in rats. In the embryo-fetal development study, avagacestat was a selective developmental toxicant with dose-related increased fetal mortality, decreased fetal growth, and increased fetal malformations and variations (primarily affecting the axial and appendicular skeletal system) at ≥3 mg/kg/day. In the female fertility and early embryonic development study, avagacestat-related reductions in female fecundity at ≥5 mg/kg/day were attributed to impaired ovarian follicular development that was reflected in dose-dependent reductions in implantation sites, litter size, and gravid uterine weights. In the male fertility and early embryonic development study, avagacestat-related effects on reproduction could not be fully assessed because of low systemic exposures achieved due to extensive metabolism and clearance of the drug. The results obtained in these studies were consistent with pharmacologically mediated inhibition of γ-secretase and resulting inhibition of Notch processing and signaling that are key for embryonic development and ovary folliculogenesis. These findings are not considered a risk for late-onset AD where the patient population is ≥65 years old most with women who are post-menopausal. However, for treatment of early onset AD with a younger patient population, there are risks for reproductive or developmental toxicities with treatment with gamma secretase inhibitors like avagacestat.
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Liu K, Ge H, Liu C, Jiang Y, Yu Y, Zhou Z. Notch-RBPJ Pathway for the Differentiation of Bone Marrow Mesenchymal Stem Cells in Femoral Head Necrosis. Int J Mol Sci 2023; 24:ijms24076295. [PMID: 37047268 PMCID: PMC10094204 DOI: 10.3390/ijms24076295] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2023] [Revised: 03/11/2023] [Accepted: 03/23/2023] [Indexed: 03/30/2023] Open
Abstract
Femoral head necrosis (FHN) is a common leg disease in broilers, resulting in economic losses in the poultry industry. The occurrence of FHN is closely related to the decrease in the number of bone marrow mesenchymal stem cells (BMSCs) and the change in differentiation direction. This study aimed to investigate the function of differentiation of BMSCs in the development of FHN. We isolated and cultured BMSCs from spontaneous FHN-affected broilers and normal broilers, assessed the ability of BMSCs into three lineages by multiple staining methods, and found that BMSCs isolated from FHN-affected broilers demonstrated enhanced lipogenic differentiation, activated Notch-RBPJ signaling pathway, and diminished osteogenic and chondrogenic differentiation. The treatment of BMSCs with methylprednisolone (MP) revealed a significant decrease in the expressions of Runx2, BMP2, Col2a1 and Aggrecan, while the expressions of p-Notch1/Notch1, Notch2 and RBPJ were increased significantly. Jagged-1 (JAG-1, Notch activator)/DAPT (γ-secretase inhibitor) could promote/inhibit the osteogenic or chondrogenic ability of MP-treated BMSCs, respectively, whereas the differentiation ability of BMSCs was restored after transfection with si-RBPJ. The above results suggest that the Notch-RBPJ pathway plays important role in FHN progression by modulating the osteogenic and chondrogenic differentiation of BMSCs.
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Zaidi M, Kim SM, Mathew M, Korkmaz F, Sultana F, Miyashita S, Gumerova AA, Frolinger T, Moldavski O, Barak O, Pallapati A, Rojekar S, Caminis J, Ginzburg Y, Ryu V, Davies TF, Lizneva D, Rosen CJ, Yuen T. Bone circuitry and interorgan skeletal crosstalk. eLife 2023; 12:83142. [PMID: 36656634 PMCID: PMC9851618 DOI: 10.7554/elife.83142] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Accepted: 12/29/2022] [Indexed: 01/20/2023] Open
Abstract
The past decade has seen significant advances in our understanding of skeletal homeostasis and the mechanisms that mediate the loss of bone integrity in disease. Recent breakthroughs have arisen mainly from identifying disease-causing mutations and modeling human bone disease in rodents, in essence, highlighting the integrative nature of skeletal physiology. It has become increasingly clear that bone cells, osteoblasts, osteoclasts, and osteocytes, communicate and regulate the fate of each other through RANK/RANKL/OPG, liver X receptors (LXRs), EphirinB2-EphB4 signaling, sphingolipids, and other membrane-associated proteins, such as semaphorins. Mounting evidence also showed that critical developmental pathways, namely, bone morphogenetic protein (BMP), NOTCH, and WNT, interact each other and play an important role in postnatal bone remodeling. The skeleton communicates not only with closely situated organs, such as bone marrow, muscle, and fat, but also with remote vital organs, such as the kidney, liver, and brain. The metabolic effect of bone-derived osteocalcin highlights a possible role of skeleton in energy homeostasis. Furthermore, studies using genetically modified rodent models disrupting the reciprocal relationship with tropic pituitary hormone and effector hormone have unraveled an independent role of pituitary hormone in skeletal remodeling beyond the role of regulating target endocrine glands. The cytokine-mediated skeletal actions and the evidence of local production of certain pituitary hormones by bone marrow-derived cells displays a unique endocrine-immune-skeletal connection. Here, we discuss recently elucidated mechanisms controlling the remodeling of bone, communication of bone cells with cells of other lineages, crosstalk between bone and vital organs, as well as opportunities for treating diseases of the skeleton.
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Affiliation(s)
- Mone Zaidi
- The Mount Sinai Bone Program, Departments of Pharmacological Sciences and of Medicine, and Center of Translational Medicine and Pharmacology, Icahn School of Medicine at Mount SinaiNew YorkUnited States
| | - Se-Min Kim
- The Mount Sinai Bone Program, Departments of Pharmacological Sciences and of Medicine, and Center of Translational Medicine and Pharmacology, Icahn School of Medicine at Mount SinaiNew YorkUnited States
| | - Mehr Mathew
- The Mount Sinai Bone Program, Departments of Pharmacological Sciences and of Medicine, and Center of Translational Medicine and Pharmacology, Icahn School of Medicine at Mount SinaiNew YorkUnited States
| | - Funda Korkmaz
- The Mount Sinai Bone Program, Departments of Pharmacological Sciences and of Medicine, and Center of Translational Medicine and Pharmacology, Icahn School of Medicine at Mount SinaiNew YorkUnited States
| | - Farhath Sultana
- The Mount Sinai Bone Program, Departments of Pharmacological Sciences and of Medicine, and Center of Translational Medicine and Pharmacology, Icahn School of Medicine at Mount SinaiNew YorkUnited States
| | - Sari Miyashita
- The Mount Sinai Bone Program, Departments of Pharmacological Sciences and of Medicine, and Center of Translational Medicine and Pharmacology, Icahn School of Medicine at Mount SinaiNew YorkUnited States
| | - Anisa Azatovna Gumerova
- The Mount Sinai Bone Program, Departments of Pharmacological Sciences and of Medicine, and Center of Translational Medicine and Pharmacology, Icahn School of Medicine at Mount SinaiNew YorkUnited States
| | - Tal Frolinger
- The Mount Sinai Bone Program, Departments of Pharmacological Sciences and of Medicine, and Center of Translational Medicine and Pharmacology, Icahn School of Medicine at Mount SinaiNew YorkUnited States
| | - Ofer Moldavski
- The Mount Sinai Bone Program, Departments of Pharmacological Sciences and of Medicine, and Center of Translational Medicine and Pharmacology, Icahn School of Medicine at Mount SinaiNew YorkUnited States
| | - Orly Barak
- The Mount Sinai Bone Program, Departments of Pharmacological Sciences and of Medicine, and Center of Translational Medicine and Pharmacology, Icahn School of Medicine at Mount SinaiNew YorkUnited States
| | - Anusha Pallapati
- The Mount Sinai Bone Program, Departments of Pharmacological Sciences and of Medicine, and Center of Translational Medicine and Pharmacology, Icahn School of Medicine at Mount SinaiNew YorkUnited States
| | - Satish Rojekar
- The Mount Sinai Bone Program, Departments of Pharmacological Sciences and of Medicine, and Center of Translational Medicine and Pharmacology, Icahn School of Medicine at Mount SinaiNew YorkUnited States
| | - John Caminis
- The Mount Sinai Bone Program, Departments of Pharmacological Sciences and of Medicine, and Center of Translational Medicine and Pharmacology, Icahn School of Medicine at Mount SinaiNew YorkUnited States
| | - Yelena Ginzburg
- The Mount Sinai Bone Program, Departments of Pharmacological Sciences and of Medicine, and Center of Translational Medicine and Pharmacology, Icahn School of Medicine at Mount SinaiNew YorkUnited States
| | - Vitaly Ryu
- The Mount Sinai Bone Program, Departments of Pharmacological Sciences and of Medicine, and Center of Translational Medicine and Pharmacology, Icahn School of Medicine at Mount SinaiNew YorkUnited States
| | - Terry F Davies
- The Mount Sinai Bone Program, Departments of Pharmacological Sciences and of Medicine, and Center of Translational Medicine and Pharmacology, Icahn School of Medicine at Mount SinaiNew YorkUnited States
| | - Daria Lizneva
- The Mount Sinai Bone Program, Departments of Pharmacological Sciences and of Medicine, and Center of Translational Medicine and Pharmacology, Icahn School of Medicine at Mount SinaiNew YorkUnited States
| | | | - Tony Yuen
- The Mount Sinai Bone Program, Departments of Pharmacological Sciences and of Medicine, and Center of Translational Medicine and Pharmacology, Icahn School of Medicine at Mount SinaiNew YorkUnited States
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EGFL7 Secreted By Human Bone Mesenchymal Stem Cells Promotes Osteoblast Differentiation Partly Via Downregulation Of Notch1-Hes1 Signaling Pathway. Stem Cell Rev Rep 2023; 19:968-982. [PMID: 36609902 DOI: 10.1007/s12015-022-10503-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/23/2022] [Indexed: 01/09/2023]
Abstract
BACKGROUND Epidermal growth factor-like domain protein 7 (EGFL7) is a secreted protein that is differentially expressed in the bone microenvironment; however, the effect of EGFL7 on the osteogenesis of human bone marrow mesenchymal stem cells (hBMSCs) is largely unknown. METHODS EGFL7 expression in the fracture microenvironment was analyzed based on the Gene Expression Omnibus (GEO) database. Knockdown of EGFL7 by small interfering RNA (siRNA) and in vitro stimulation with recombinant human EGFL7 (rhEGFL7) protein were used to assess alterations in downstream signaling and changes in the osteogenic differentiation and proliferation of hBMSCs. A γ-secretase inhibitor was used to further explore whether inhibition of Notch signaling rescued the osteogenic-inhibitory effect of EGFL7 knockdown in hBMSCs. A femoral defect model was established to verify the effect of recombinant mouse EGFL7 on bone healing in vivo. RESULTS EGFL7 expression increased during hBMSC osteogenesis. Knockdown of EGFL7 impaired hBMSC osteogenesis and activated Notch1/NICD/Hes1 signaling. rhEGFL7 promoted hBMSC osteogenesis and downregulated Notch1 signaling. The osteoblast-inhibitory effect of EGFL7 knockdown was rescued by Notch1 signaling inhibition. Recombinant EGFL7 led to enhanced bone healing in mice with femoral defects. CONCLUSIONS EGFL7 promotes osteogenesis of hBMSCs partly via downregulation of Notch1 signaling.
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Barik A, Kirtania MD. In-Vitro and In-Vivo Tracking of Cell-Biomaterial Interaction to Monitor the Process of Bone Regeneration. Regen Med 2023. [DOI: 10.1007/978-981-19-6008-6_15] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023] Open
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Ang PS, Matrongolo MJ, Zietowski ML, Nathan SL, Reid RR, Tischfield MA. Cranium growth, patterning and homeostasis. Development 2022; 149:dev201017. [PMID: 36408946 PMCID: PMC9793421 DOI: 10.1242/dev.201017] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Craniofacial development requires precise spatiotemporal regulation of multiple signaling pathways that crosstalk to coordinate the growth and patterning of the skull with surrounding tissues. Recent insights into these signaling pathways and previously uncharacterized progenitor cell populations have refined our understanding of skull patterning, bone mineralization and tissue homeostasis. Here, we touch upon classical studies and recent advances with an emphasis on developmental and signaling mechanisms that regulate the osteoblast lineage for the calvaria, which forms the roof of the skull. We highlight studies that illustrate the roles of osteoprogenitor cells and cranial suture-derived stem cells for proper calvarial growth and homeostasis. We also discuss genes and signaling pathways that control suture patency and highlight how perturbing the molecular regulation of these pathways leads to craniosynostosis. Finally, we discuss the recently discovered tissue and signaling interactions that integrate skull and cerebrovascular development, and the potential implications for both cerebrospinal fluid hydrodynamics and brain waste clearance in craniosynostosis.
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Affiliation(s)
- Phillip S. Ang
- Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ 08854, USA
- University of Chicago Pritzker School of Medicine, Chicago, IL 60637, USA
| | - Matt J. Matrongolo
- Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ 08854, USA
- Child Health Institute of New Jersey, New Brunswick, NJ 08901, USA
| | | | - Shelby L. Nathan
- Laboratory of Craniofacial Biology and Development, Section of Plastic Surgery, Department of Surgery, University of Chicago Medicine, Chicago, IL 60637, USA
| | - Russell R. Reid
- Laboratory of Craniofacial Biology and Development, Section of Plastic Surgery, Department of Surgery, University of Chicago Medicine, Chicago, IL 60637, USA
| | - Max A. Tischfield
- Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ 08854, USA
- Child Health Institute of New Jersey, New Brunswick, NJ 08901, USA
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Long L, Wang X, Lei Y, Guo S, Wang C, Dai W, Lin B, Xie M, Xu H, Li S. Icariin: A Potential Alternative Against Osteoporosis. Nat Prod Commun 2022. [DOI: 10.1177/1934578x221134881] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Osteoporosis is a metabolic skeletal disorder characterized by increased fragility and fracture risk as s result of reduced bone mineral density and microstructural destruction and caused a heavy burden on families and society. Current medicines, on the other hand, have some limitations, with side effects and doubts regarding long-term efficacy being highlighted. Studies seeking for natural constituents as potential treatment options therefore come into focus. Icariin is a phytochemical derived from a traditional Chinese medicine, Herba epimedium, that has been used to treat orthopedic disorders in ancient China for thousands of years, including osteoporosis, osteoarthritis, and fracture. Icariin belongs to a category of prenylated flavonoids and has been shown to help reduce osteoporosis bone loss while having relatively low side effects. Icariin's anti-osteoporosis properties manifest in a variety of ways, like promoting osteogenesis, suppressing osteoclastogenesis and bone resorption, regulating migration, proliferation, and differentiation of mesenchymal stem cells, enhancing angiogenesis, anti-inflammation, and antioxidation. These procedures entail a slew of critical signaling pathways, such as PPARγ, ERα/AKT/β-catenin, and MAPK. Therefore, icariin can be an applicable alternative to improve osteoporosis although the underlying mechanisms have yet to be fully understood. In this study, we searched using the terms “icariin” and “osteoporosis,” and included 64 articles meeting the inclusion criteria and reviewed the research of icariin in anti-osteoporosis over the last 10 years, and discussed new prospects for future study. Therefore, this review may provide some references for further studies.
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Affiliation(s)
- Longhai Long
- Spinal Surgery Department, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
| | - Xiaoqiang Wang
- Spinal Surgery Department, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
| | - Yang Lei
- Spinal Surgery Department, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
| | - Sheng Guo
- Spinal Surgery Department, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
| | - Chenglong Wang
- Spinal Surgery Department, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
| | - Wenbin Dai
- Geriatric Department, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
| | - Birong Lin
- Spinal Surgery Department, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
| | - Mingzhong Xie
- Spinal Surgery Department, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
| | - Houping Xu
- Department of Preventive Treatment Center, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
| | - Sen Li
- Spinal Surgery Department, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
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Zheng W, Bai Z, Huang S, Jiang K, Liu L, Wang X. The Effect of Angiogenesis-Based Scaffold of MesoporousBioactive Glass Nanofiber on Osteogenesis. Int J Mol Sci 2022; 23:12670. [PMID: 36293527 PMCID: PMC9604128 DOI: 10.3390/ijms232012670] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Revised: 10/17/2022] [Accepted: 10/19/2022] [Indexed: 11/23/2022] Open
Abstract
There is still an urgent need for more efficient biological scaffolds to promote the healing of bone defects. Vessels can accelerate bone growth and regeneration by transporting nutrients, which is an excellent method to jointly increase osteogenesis and angiogenesis in bone regeneration. Therefore, we aimed to prepare a composite scaffold that could promote osteogenesis with angiogenesis to enhance bone defect repair. Here, we report that scaffolds were prepared by coaxial electrospinning with mesoporous bioactive glass modified with amino (MBG-NH2) adsorbing insulin-like growth factor-1 (IGF-1) as the core and silk fibroin (SF) adsorbing vascular endothelial growth factor (VEGF) as the shell. These scaffolds were named MBG-NH2/IGF@SF/VEGF and might be used as repair materials to promote bone defect repair. Interestingly, we found that the MBG-NH2/IGF@SF/VEGF scaffolds had nano-scale morphology and high porosity, as well as enough mechanical strength to support the tissue. Moreover, MBG-NH2 could sustain the release of IGF-1 to achieve long-term repair. Additionally, the MBG-NH2/IGF@SF/VEGF scaffolds could significantly promote the mRNA expression levels of osteogenic marker genes and the protein expression levels of Bmp2 and Runx2 in bone marrow mesenchymal stem cells (BMSCs). Meanwhile, the MBG-NH2/IGF@SF/VEGF scaffolds promoted osteogenesis by simulating Runx2 transcription activity through the phosphorylated Erk1/2-activated pathway. Intriguingly, the MBG-NH2/IGF@SF/VEGF scaffolds could also significantly promote the mRNA expression level of angiogenesis marker genes and the protein expression level of CD31. Furthermore, RNA sequencing verified that the MBG-NH2/IGF@SF/VEGF scaffolds had excellent performance in promoting bone defect repair and angiogenesis. Consistent with these observations, we found that the MBG-NH2/IGF@SF/VEGF scaffolds demonstrated a good repair effect on a critical skull defect in mice in vivo, which not only promoted the formation of blood vessels in the haversian canal but also accelerated the bone repair process. We concluded that these MBG-NH2/IGF@SF/VEGF scaffolds could promote bone defect repair under accelerating angiogenesis. Our finding provides a new potential biomaterial for bone tissue engineering.
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Affiliation(s)
| | | | | | | | - Long Liu
- Department of Biology and Chemistry, College of Science, National University of Defense Technology, Changsha 410073, China
| | - Xiaoyan Wang
- Correspondence: (L.L.); (X.W.); Tel.: +86-0731-8700-1351 (X.W.); Fax: +86-0731-8700-1040 (X.W.)
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Liu Y, Niu P, Zhou M, Xue H. The role of proteoglycan form of DMP1 in cranial repair. BMC Mol Cell Biol 2022; 23:43. [PMID: 36175851 PMCID: PMC9524138 DOI: 10.1186/s12860-022-00443-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2022] [Accepted: 09/20/2022] [Indexed: 11/11/2022] Open
Abstract
Background The cranial region is a complex set of blood vessels, cartilage, nerves and soft tissues. The reconstruction of cranial defects caused by trauma, congenital defects and surgical procedures presents clinical challenges. Our previous data showed that deficiency of the proteoglycan (PG) form of dentin matrix protein 1 (DMP1-PG) could lead to abnormal cranial development. In addition, DMP1-PG was highly expressed in the cranial defect areas. The present study aimed to investigate the potential role of DMP1-PG in intramembranous ossification in cranial defect repair. Methods Mouse cranial defect models were established by using wild- type (WT) and DMP1-PG point mutation mice. Microcomputed tomography (micro-CT) and histological staining were performed to assess the extent of repair. Immunofluorescence assays and real-time quantitative polymerase chain reaction (RT‒qPCR) were applied to detect the differentially expressed osteogenic markers. RNA sequencing was performed to probe the molecular mechanism of DMP1-PG in regulating defect healing. Results A delayed healing process and an abnormal osteogenic capacity of primary osteoblasts were observed in DMP1-PG point mutation mice. Furthermore, impaired inflammatory signaling pathways were detected by using RNA transcription analysis of this model. Conclusions Our data indicate that DMP1-PG is an indispensable positive regulator during cranial defect healing. Supplementary Information The online version contains supplementary material available at 10.1186/s12860-022-00443-4.
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Progress and Current Status in Hajdu-Cheney Syndrome with Focus on Novel Genetic Research. Int J Mol Sci 2022; 23:ijms231911374. [PMID: 36232677 PMCID: PMC9570194 DOI: 10.3390/ijms231911374] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 09/16/2022] [Accepted: 09/19/2022] [Indexed: 12/02/2022] Open
Abstract
Hajdu-Cheney syndrome (HCS) is a rare autosomal dominant manifestation of a congenital genetic disorder caused by a mutation in the NOTCH2 gene. NOTCH signaling has variations from NOTCH 1 to 4 and maintains homeostasis by determining and regulating the proliferation and differentiation of various cells. In HCS, the over-accumulated NOTCH2 causes abnormal bone resorption due to its continuous excessive signaling. HCS is characterized by progressive bone destruction, has complex wide-range clinical manifestations, and significantly impacts the patient’s quality of life. However, no effective treatment has been established for HCS to date. There are genetic variants of NOTCH2 that have been reported in the ClinVar database of the U.S. National Institutes of Health. In total, 26 mutant variants were detected based on the American College of Medical Genetics and Genomics (ACMC). To date, there has been no comprehensive compilation of HCS mutations. In this review, we provide the most comprehensive list possible of HCS variants, nucleotide changes, amino acid definitions, and molecular consequences reported to date, following the ACMC guidelines.
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Filipović M, Flegar D, Šućur A, Šisl D, Kavazović I, Antica M, Kelava T, Kovačić N, Grčević D. Inhibition of Notch Signaling Stimulates Osteoclastogenesis From the Common Trilineage Progenitor Under Inflammatory Conditions. Front Immunol 2022; 13:902947. [PMID: 35865541 PMCID: PMC9294223 DOI: 10.3389/fimmu.2022.902947] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Accepted: 05/25/2022] [Indexed: 11/13/2022] Open
Abstract
Osteoclasts, macrophages and dendritic cells (DCs) can be derived from a common trilineage myeloid progenitor of hematopoietic origin. Progenitor commitment is susceptible to regulation through Notch signaling. Our aim was to determine the effects of Notch modulation on trilineage progenitor commitment and functional properties of differentiated cells under inflammatory conditions. We used the conditional inducible CX3CR1CreERT2 mouse strain to achieve overexpression of the Notch 1 intracellular domain (NICD1) or to inhibit Notch signaling via deletion of the transcription factor RBP-J in a bone marrow population, used as a source of the trilineage progenitor (CD45+Ly6G−CD3−B220−NK1.1−CD11b–/loCD115+). Cre-recombinase, under the control of the CX3CR1 promoter, expressed in the monocyte/macrophage lineage, was induced in vitro by 4-hydroxytamoxifen. Differentiation of osteoclasts was induced by M-CSF/RANKL; macrophages by M-CSF; DCs by IL-4/GM-CSF, and inflammation by LPS. Functionally, DCs were tested for the ability to process and present antigen, macrophages to phagocytose E. coli particles, and osteoclasts to resorb bone and express tartrate-resistant acid phosphatase (TRAP). We found that Notch 1 signal activation suppressed osteoclast formation, whereas disruption of the Notch canonical pathway enhanced osteoclastogenesis, resulting in a higher number and size of osteoclasts. RANK protein and Ctsk gene expression were upregulated in osteoclastogenic cultures from RBP-J+ mice, with the opposing results in NICD1+ mice. Notch modulation did not affect the number of in vitro differentiated macrophages and DCs. However, RBP-J deletion stimulated Il12b and Cd86 expression in macrophages and DCs, respectively. Functional assays under inflammatory conditions confirmed that Notch silencing amplifies TRAP expression by osteoclasts, whereas the enhanced phagocytosis by macrophages was observed in both NICD1+ and RBP-J+ strains. Finally, antigen presentation by LPS-stimulated DCs was significantly downregulated with NICD1 overexpression. This experimental setting allowed us to define a cell-autonomous response to Notch signaling at the trilineage progenitor stage. Although Notch signaling modulation affected the activity of all three lineages, the major effect was observed in osteoclasts, resulting in enhanced differentiation and function with inhibition of canonical Notch signaling. Our results indicate that Notch signaling participates as the negative regulator of osteoclast activity during inflammation, which may be relevant in immune and bone diseases.
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Affiliation(s)
- Maša Filipović
- Department of Physiology and Immunology, University of Zagreb School of Medicine, Zagreb, Croatia
- Laboratory for Molecular Immunology, Croatian Institute for Brain Research, University of Zagreb School of Medicine, Zagreb, Croatia
| | - Darja Flegar
- Department of Physiology and Immunology, University of Zagreb School of Medicine, Zagreb, Croatia
- Laboratory for Molecular Immunology, Croatian Institute for Brain Research, University of Zagreb School of Medicine, Zagreb, Croatia
| | - Alan Šućur
- Department of Physiology and Immunology, University of Zagreb School of Medicine, Zagreb, Croatia
- Laboratory for Molecular Immunology, Croatian Institute for Brain Research, University of Zagreb School of Medicine, Zagreb, Croatia
| | - Dino Šisl
- Department of Physiology and Immunology, University of Zagreb School of Medicine, Zagreb, Croatia
- Laboratory for Molecular Immunology, Croatian Institute for Brain Research, University of Zagreb School of Medicine, Zagreb, Croatia
| | - Inga Kavazović
- Department of Histology and Embryology, Faculty of Medicine, University of Rijeka, Rijeka, Croatia
| | | | - Tomislav Kelava
- Department of Physiology and Immunology, University of Zagreb School of Medicine, Zagreb, Croatia
- Laboratory for Molecular Immunology, Croatian Institute for Brain Research, University of Zagreb School of Medicine, Zagreb, Croatia
| | - Nataša Kovačić
- Laboratory for Molecular Immunology, Croatian Institute for Brain Research, University of Zagreb School of Medicine, Zagreb, Croatia
- Department of Anatomy, University of Zagreb School of Medicine, Zagreb, Croatia
| | - Danka Grčević
- Department of Physiology and Immunology, University of Zagreb School of Medicine, Zagreb, Croatia
- Laboratory for Molecular Immunology, Croatian Institute for Brain Research, University of Zagreb School of Medicine, Zagreb, Croatia
- *Correspondence: Danka Grčević,
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Cortés-Martín J, Díaz-Rodríguez L, Piqueras-Sola B, Sánchez-García JC, Menor-Rodríguez MJ, Rodríguez-Blanque R. Nursing Care Plan for Patients with Hajdu-Cheney Syndrome. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2022; 19:7489. [PMID: 35742738 PMCID: PMC9223558 DOI: 10.3390/ijerph19127489] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Revised: 06/15/2022] [Accepted: 06/16/2022] [Indexed: 02/01/2023]
Abstract
Hajdu-Cheney syndrome is a rare genetic disease. Its main features include phenotypic variability, age-dependent progression and the presence of acroosteolysis of the distal phalanges and generalized osteoporosis, which have significant disabling potential. Currently, there is no effective curative treatment, so nursing care is essential to ensure the maintenance of the quality of life of these patients. The main objective of this study was to establish a specific standardized nursing care plan using the NANDA-NIC-NOC taxonomy. The application of a care plan as such would improve the quality of life of patients affected by this rare disease, will contribute to increasing healthcare professionals' knowledge on this matter and will support future studies on this disease.
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Affiliation(s)
- Jonathan Cortés-Martín
- Research Group CTS1068, Andalusia Research Plan, Junta de Andalucía, 18014 Granada, Spain; (J.C.-M.); (L.D.-R.); (B.P.-S.); (R.R.-B.)
- Faculty of Health Sciences, School of Nursing, University of Granada, 18071 Granada, Spain
| | - Lourdes Díaz-Rodríguez
- Research Group CTS1068, Andalusia Research Plan, Junta de Andalucía, 18014 Granada, Spain; (J.C.-M.); (L.D.-R.); (B.P.-S.); (R.R.-B.)
- Faculty of Health Sciences, School of Nursing, University of Granada, 18071 Granada, Spain
| | - Beatriz Piqueras-Sola
- Research Group CTS1068, Andalusia Research Plan, Junta de Andalucía, 18014 Granada, Spain; (J.C.-M.); (L.D.-R.); (B.P.-S.); (R.R.-B.)
- Hospital University Virgen de las Nieves, 18014 Granada, Spain
| | - Juan Carlos Sánchez-García
- Research Group CTS1068, Andalusia Research Plan, Junta de Andalucía, 18014 Granada, Spain; (J.C.-M.); (L.D.-R.); (B.P.-S.); (R.R.-B.)
- Faculty of Health Sciences, School of Nursing, University of Granada, 18071 Granada, Spain
| | - María José Menor-Rodríguez
- Subdirectora de Humanización y Atención al Ciudadano, Área Sanitaria Santiago-Barbanza, 15706 Santiago de Compostela, Spain;
| | - Raquel Rodríguez-Blanque
- Research Group CTS1068, Andalusia Research Plan, Junta de Andalucía, 18014 Granada, Spain; (J.C.-M.); (L.D.-R.); (B.P.-S.); (R.R.-B.)
- Faculty of Health Sciences, School of Nursing, University of Granada, 18071 Granada, Spain
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Notch2 Blockade Mitigates Methotrexate Chemotherapy-Induced Bone Loss and Marrow Adiposity. Cells 2022; 11:cells11091521. [PMID: 35563828 PMCID: PMC9103078 DOI: 10.3390/cells11091521] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Revised: 04/27/2022] [Accepted: 04/28/2022] [Indexed: 11/17/2022] Open
Abstract
Childhood cancer methotrexate (MTX) chemotherapy often causes bone growth impairments, bone loss, and increased risks of fractures during or after treatment, for which the pathobiology is unclear and there is a lack of specific treatment. Our time course analyses of long bones from rats receiving intensive MTX treatment (mimicking a clinical protocol) found decreased trabecular bone volume, increased osteoclast formation and activity, increased adipogenesis in the expense of osteogenesis from the bone marrow stromal cells at days 6 and 9 following the first of five daily MTX doses. For exploring potential mechanisms, PCR array expression of 91 key factors regulating bone homeostasis was screened with the bone samples, which revealed MTX treatment-induced upregulation of Notch receptor NOTCH2, activation of which is known to be critical in skeletal development and bone homeostasis. Consistently, increased Notch2 activation in bones of MTX-treated rats was confirmed, accompanied by increased expression of Notch2 intracellular domain protein and Notch target genes HEY1, HES1 and HEYL. To confirm the roles of Notch2 signalling, a neutralising anti-Notch2 antibody or a control IgG was administered to rats during MTX treatment. Microcomputed tomography analyses demonstrated that trabecular bone volume was preserved by MTX+anti-Notch2 antibody treatment. Anti-Notch2 antibody treatment ameliorated MTX treatment-induced increases in osteoclast density and NFATc1 and RANKL expression, and attenuated MTX-induced bone marrow adiposity via regulating Wnt/β-catenin signalling and PPARγ expression. Thus, Notch2 signalling plays an important role in mediating MTX treatment-induced bone loss and bone marrow adiposity, and targeting Notch2 could be a potential therapeutic option.
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Wang P, Wang X, Wang B, Li X, Xie Z, Chen J, Honjo T, Tu X. 3D printing of osteocytic Dll4 integrated with PCL for cell fate determination towards osteoblasts in vitro. Biodes Manuf 2022. [DOI: 10.1007/s42242-022-00196-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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Dai X, Liu S, Cheng L, Huang T, Guo H, Wang D, Xia M, Ling W, Xiao Y. Epigenetic Upregulation of H19 and AMPK Inhibition Concurrently Contribute to S-Adenosylhomocysteine Hydrolase Deficiency-Promoted Atherosclerotic Calcification. Circ Res 2022; 130:1565-1582. [PMID: 35410483 DOI: 10.1161/circresaha.121.320251] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
BACKGROUND S-adenosylhomocysteine (SAH) is a risk factor of cardiovascular disease; inhibition of SAH hydrolase (SAHH) results in SAH accumulation and induces endothelial dysfunction and atherosclerosis. However, the effect and mechanism of SAHH in atherosclerotic calcification is still unclear. We aimed to explore the role and mechanism of SAHH in atherosclerotic calcification. METHODS The relationship between SAHH and atherosclerotic calcification was investigated in patients with coronary atherosclerotic calcification. Different in vivo genetic models were used to examine the effect of SAHH deficiency on atherosclerotic calcification. Human aortic and murine vascular smooth muscle cells (VSMCs) were cultured to explore the underlying mechanism of SAHH on osteoblastic differentiation of VSMCs. RESULTS The expression and activity of SAHH were decreased in calcified human coronary arteries and inversely associated with coronary atherosclerotic calcification severity, whereas plasma SAH and total homocysteine levels were positively associated with coronary atherosclerotic calcification severity. Heterozygote knockout of SAHH promoted atherosclerotic calcification. Specifically, VSMC-deficient but not endothelial cell-deficient or macrophage-deficient SAHH promoted atherosclerotic calcification. Mechanistically, SAHH deficiency accumulated SAH levels and induced H19-mediated Runx2 (runt-related transcription factor 2)-dependent osteoblastic differentiation of VSMCs by inhibiting DNMT3b (DNA methyltransferase 3 beta) and leading to hypomethylation of the H19 promoter. On the other hand, SAHH deficiency resulted in lower intracellular levels of adenosine and reduced AMPK (AMP-activated protein kinase) activation. Adenosine supplementation activated AMPK and abolished SAHH deficiency-induced expression of H19 and Runx2 and osteoblastic differentiation of VSMCs. Finally, AMPK activation by adenosine inhibited H19 expression by inducing Sirt1-mediated histone H3 hypoacetylation and DNMT3b-mediated hypermethylation of the H19 promoter in SAHH deficiency VSMCs. CONCLUSIONS We have confirmed a novel correlation between SAHH deficiency and atherosclerotic calcification and clarified a new mechanism that epigenetic upregulation of H19 and AMPK inhibition concurrently contribute to SAHH deficiency-promoted Runx2-dependent atherosclerotic calcification.
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Affiliation(s)
- Xin Dai
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China (X.D., S.L., L.C., T.H., Y.X.)
| | - Si Liu
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China (X.D., S.L., L.C., T.H., Y.X.)
| | - Lokyu Cheng
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China (X.D., S.L., L.C., T.H., Y.X.)
| | - Ting Huang
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China (X.D., S.L., L.C., T.H., Y.X.)
| | - Honghui Guo
- Department of Nutrition, School of Public Health, Guangdong Medical University, Dongguan, China (H.G.)
| | - Dongliang Wang
- Department of Nutrition, Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-sen University, Guangzhou, China (D.W., M.X., W.L.)
| | - Min Xia
- Department of Nutrition, Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-sen University, Guangzhou, China (D.W., M.X., W.L.)
| | - Wenhua Ling
- Department of Nutrition, Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-sen University, Guangzhou, China (D.W., M.X., W.L.)
| | - Yunjun Xiao
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China (X.D., S.L., L.C., T.H., Y.X.)
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Zhang D, Guo X, Zong X, Du H, Zhao J, Du L, Cao C, Jin X, Song G. Study on the difference of osteogenesis and Notch signaling pathway expression in biphasic calcium-phosphorus ceramic granule materials with different microstructure. J Biomed Mater Res B Appl Biomater 2022; 110:2028-2038. [PMID: 35377532 DOI: 10.1002/jbm.b.35057] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Revised: 02/27/2022] [Accepted: 03/03/2022] [Indexed: 11/12/2022]
Abstract
Different microstructures including micropore diameter, micropore volume, and micropore area of biphasic calcium phosphate (BCP, hydroxyapatite: β-tricalcium phosphate = 8:2) ceramics granules were obtained by varying their sintering temperatures. Sprague-Dawley rat bone marrow-derived stem cells (BMSCs) were co-cultured with BCPs in vitro study and the BMSCs showed different degrees of proliferative activity under the influence of three materials. Cell proliferation and vitality were assessed. Three kinds of BCPs were implanted in the dorsal muscle of beagle dogs. At 1, 2, and 3 months, histological analyses were conducted to estimate the rate of osteogenesis. Expression of Notch pathway genes and osteogenic-related genes were detected by quantitative real-time polymerase chain reaction (q-rtPCR). The proportion of osteogenesis area increased to:48.75 ± 4.20%, 29.48 ± 1.55%, and 26.58 ± 3.86% at 3 months after the implantation (1050, 1150, 1250). Significant differences were observed in the upregulation of Notch pathway genes among different BCPs. BCPs with different micropore diameters have different ectopic osteogenesis effects and led to up-regulation of the Notch signaling pathway genes to different extents.
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Affiliation(s)
- Dong Zhang
- 16th Department, Plastic Surgery Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Xiaoshuang Guo
- 16th Department, Plastic Surgery Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Xianlei Zong
- 16th Department, Plastic Surgery Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Hong Du
- 16th Department, Plastic Surgery Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Jingyi Zhao
- 16th Department, Plastic Surgery Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Le Du
- 16th Department, Plastic Surgery Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Chunyan Cao
- Animal Lab Center, Plastic Surgery Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Xiaolei Jin
- 16th Department, Plastic Surgery Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Guodong Song
- 16th Department, Plastic Surgery Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
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Fehsel K, Christl J. Comorbidity of osteoporosis and Alzheimer's disease: Is `AKT `-ing on cellular glucose uptake the missing link? Ageing Res Rev 2022; 76:101592. [PMID: 35192961 DOI: 10.1016/j.arr.2022.101592] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Revised: 02/14/2022] [Accepted: 02/16/2022] [Indexed: 02/08/2023]
Abstract
Osteoporosis and Alzheimer's disease (AD) are both degenerative diseases. Osteoporosis often proceeds cognitive deficits, and multiple studies have revealed common triggers that lead to energy deficits in brain and bone. Risk factors for osteoporosis and AD, such as obesity, type 2 diabetes, aging, chemotherapy, vitamin deficiency, alcohol abuse, and apolipoprotein Eε4 and/or Il-6 gene variants, reduce cellular glucose uptake, and protective factors, such as estrogen, insulin, exercise, mammalian target of rapamycin inhibitors, hydrogen sulfide, and most phytochemicals, increase uptake. Glucose uptake is a fine-tuned process that depends on an abundance of glucose transporters (Gluts) on the cell surface. Gluts are stored in vesicles under the plasma membrane, and protective factors cause these vesicles to fuse with the membrane, resulting in presentation of Gluts on the cell surface. This translocation depends mainly on AKT kinase signaling and can be affected by a range of factors. Reduced AKT kinase signaling results in intracellular glucose deprivation, which causes endoplasmic reticulum stress and iron depletion, leading to activation of HIF-1α, the transcription factor necessary for higher Glut expression. The link between diseases and aging is a topic of growing interest. Here, we show that diseases that affect the same biochemical pathways tend to co-occur, which may explain why osteoporosis and/or diabetes are often associated with AD.
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Bae Y, Zeng H, Chen Y, Ketkar S, Munivez E, Yu Z, Gannon FH, Lee BH.
miRNA
‐34c
suppresses osteosarcoma progression
in vivo
by targeting Notch and
E2F. JBMR Plus 2022; 6:e10623. [PMID: 35509638 PMCID: PMC9059472 DOI: 10.1002/jbm4.10623] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Accepted: 03/09/2022] [Indexed: 11/16/2022] Open
Abstract
The expression of microRNAs (miRNAs) is dysregulated in many types of cancers including osteosarcoma (OS) due to genetic and epigenetic alterations. Among these, miR‐34c, an effector of tumor suppressor P53 and an upstream negative regulator of Notch signaling in osteoblast differentiation, is dysregulated in OS. Here, we demonstrated a tumor suppressive role of miR‐34c in OS progression using in vitro assays and in vivo genetic mouse models. We found that miR‐34c inhibits the proliferation and the invasion of metastatic OS cells, which resulted in reduction of the tumor burden and increased overall survival in an orthotopic xenograft model. Moreover, the osteoblast‐specific overexpression of miR‐34c increased survival in the osteoblast specific p53 mutant OS mouse model. We found that miR‐34c regulates the transcription of several genes in Notch signaling (NOTCH1, JAG1, and HEY2) and in p53‐mediated cell cycle and apoptosis (CCNE2, E2F5, E2F2, and HDAC1). More interestingly, we found that the metastatic‐free survival probability was increased among a patient cohort from Therapeutically Applicable Research to Generate Effective Treatments (TARGET) OS, which has lower expression of direct targets of miR‐34c that was identified in our transcriptome analysis, such as E2F5 and NOTCH1. In conclusion, we demonstrate that miR‐34c is a tumor suppressive miRNA in OS progression in vivo. In addition, we highlight the therapeutic potential of targeting miR‐34c in OS. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
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Affiliation(s)
- Yangjin Bae
- Department of Molecular and Human Genetics Baylor College of Medicine Houston TX
| | - Huan‐Chang Zeng
- Department of Molecular and Human Genetics Baylor College of Medicine Houston TX
| | - Yi‐Ting Chen
- Integrative Molecular and Biomedical Sciences Program Baylor College of Medicine Houston TX
| | - Shamika Ketkar
- Department of Molecular and Human Genetics Baylor College of Medicine Houston TX
| | - Elda Munivez
- Department of Molecular and Human Genetics Baylor College of Medicine Houston TX
| | - Zhiyin Yu
- Department of Molecular and Human Genetics Baylor College of Medicine Houston TX
| | - Francis H. Gannon
- Department of Pathology and Immunology Baylor College of Medicine Houston TX
| | - Brendan H. Lee
- Department of Molecular and Human Genetics Baylor College of Medicine Houston TX
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Thomas S, Jaganathan BG. Signaling network regulating osteogenesis in mesenchymal stem cells. J Cell Commun Signal 2022; 16:47-61. [PMID: 34236594 PMCID: PMC8688675 DOI: 10.1007/s12079-021-00635-1] [Citation(s) in RCA: 66] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Accepted: 06/30/2021] [Indexed: 02/06/2023] Open
Abstract
Osteogenesis is an important developmental event that results in bone formation. Bone forming cells or osteoblasts develop from mesenchymal stem cells (MSCs) through a highly controlled process regulated by several signaling pathways. The osteogenic lineage commitment of MSCs is controlled by cell-cell interactions, paracrine factors, mechanical signals, hormones, and cytokines present in their niche, which activate a plethora of signaling molecules belonging to bone morphogenetic proteins, Wnt, Hedgehog, and Notch signaling. These signaling pathways individually as well as in coordination with other signaling molecules, regulate the osteogenic lineage commitment of MSCs by activating several osteo-lineage specific transcription factors. Here, we discuss the key signaling pathways that regulate osteogenic differentiation of MSCs and the cross-talk between them during osteogenic differentiation. We also discuss how these signaling pathways can be modified for therapy for bone repair and regeneration.
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Affiliation(s)
- Sachin Thomas
- Stem Cells and Cancer Biology Research Group, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam, 781039, India
| | - Bithiah Grace Jaganathan
- Stem Cells and Cancer Biology Research Group, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam, 781039, India.
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Mo C, Guo J, Qin J, Zhang X, Sun Y, Wei H, Cao D, Zhang Y, Zhao C, Xiong Y, Zhang Y, Sun Y, Shen L, Yue R. Single-cell transcriptomics of LepR-positive skeletal cells reveals heterogeneous stress-dependent stem and progenitor pools. EMBO J 2022; 41:e108415. [PMID: 34957577 PMCID: PMC8844986 DOI: 10.15252/embj.2021108415] [Citation(s) in RCA: 52] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Revised: 11/17/2021] [Accepted: 11/18/2021] [Indexed: 12/31/2022] Open
Abstract
Leptin receptor (LepR)-positive cells are key components of the bone marrow hematopoietic microenvironment, and highly enrich skeletal stem and progenitor cells that maintain homeostasis of the adult skeleton. However, the heterogeneity and lineage hierarchy within this population has been elusive. Using genetic lineage tracing and single-cell RNA sequencing, we found that Lepr-Cre labels most bone marrow stromal cells and osteogenic lineage cells in adult long bones. Integrated analysis of Lepr-Cre-traced cells under homeostatic and stress conditions revealed dynamic changes of the adipogenic, osteogenic, and periosteal lineages. Importantly, we discovered a Notch3+ bone marrow sub-population that is slow-cycling and closely associated with the vasculatures, as well as key transcriptional networks promoting osteo-chondrogenic differentiation. We also identified a Sca-1+ periosteal sub-population with high clonogenic activity but limited osteo-chondrogenic potential. Together, we mapped the transcriptomic landscape of adult LepR+ stem and progenitor cells and uncovered cellular and molecular mechanisms underlying their maintenance and lineage specification.
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Affiliation(s)
- Chunyang Mo
- Institute for Regenerative MedicineShanghai East HospitalFrontier Science Center for Stem Cell ResearchShanghai Key Laboratory of Signaling and Disease ResearchSchool of Life Sciences and TechnologyTongji UniversityShanghaiChina
| | - Jingxin Guo
- MOE Key Laboratory of Biosystems Homeostasis & Protection and Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences InstituteZhejiang UniversityHangzhouChina
- Department of Orthopedics Surgery2nd Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhouChina
| | - Jiachen Qin
- Institute for Regenerative MedicineShanghai East HospitalFrontier Science Center for Stem Cell ResearchShanghai Key Laboratory of Signaling and Disease ResearchSchool of Life Sciences and TechnologyTongji UniversityShanghaiChina
| | - Xiaoying Zhang
- Institute for Regenerative MedicineShanghai East HospitalFrontier Science Center for Stem Cell ResearchShanghai Key Laboratory of Signaling and Disease ResearchSchool of Life Sciences and TechnologyTongji UniversityShanghaiChina
| | - Yuxi Sun
- Department of CardiologyShanghai Tenth People's HospitalTongji University School of MedicineShanghaiChina
| | - Hanjing Wei
- Institute for Regenerative MedicineShanghai East HospitalFrontier Science Center for Stem Cell ResearchShanghai Key Laboratory of Signaling and Disease ResearchSchool of Life Sciences and TechnologyTongji UniversityShanghaiChina
| | - Dandan Cao
- Institute for Regenerative MedicineShanghai East HospitalFrontier Science Center for Stem Cell ResearchShanghai Key Laboratory of Signaling and Disease ResearchSchool of Life Sciences and TechnologyTongji UniversityShanghaiChina
| | - Yiying Zhang
- Institute for Regenerative MedicineShanghai East HospitalFrontier Science Center for Stem Cell ResearchShanghai Key Laboratory of Signaling and Disease ResearchSchool of Life Sciences and TechnologyTongji UniversityShanghaiChina
| | - Chengchen Zhao
- Institute for Regenerative MedicineShanghai East HospitalFrontier Science Center for Stem Cell ResearchShanghai Key Laboratory of Signaling and Disease ResearchSchool of Life Sciences and TechnologyTongji UniversityShanghaiChina
| | - Yanhong Xiong
- Institute for Regenerative MedicineShanghai East HospitalFrontier Science Center for Stem Cell ResearchShanghai Key Laboratory of Signaling and Disease ResearchSchool of Life Sciences and TechnologyTongji UniversityShanghaiChina
| | - Yong Zhang
- Institute for Regenerative MedicineShanghai East HospitalFrontier Science Center for Stem Cell ResearchShanghai Key Laboratory of Signaling and Disease ResearchSchool of Life Sciences and TechnologyTongji UniversityShanghaiChina
| | - Yao Sun
- Department of ImplantologySchool & Hospital of StomatologyShanghai Engineering Research Center of Tooth Restoration and RegenerationTongji UniversityShanghaiChina
| | - Li Shen
- MOE Key Laboratory of Biosystems Homeostasis & Protection and Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences InstituteZhejiang UniversityHangzhouChina
- Department of Orthopedics Surgery2nd Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhouChina
- Hangzhou Innovation CenterZhejiang UniversityHangzhouChina
| | - Rui Yue
- Institute for Regenerative MedicineShanghai East HospitalFrontier Science Center for Stem Cell ResearchShanghai Key Laboratory of Signaling and Disease ResearchSchool of Life Sciences and TechnologyTongji UniversityShanghaiChina
- Shanghai Institute of Stem Cell Research and Clinical TranslationShanghaiChina
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50
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Xu C, Dinh VV, Kruse K, Jeong HW, Watson EC, Adams S, Berkenfeld F, Stehling M, Rasouli SJ, Fan R, Chen R, Bedzhov I, Chen Q, Kato K, Pitulescu ME, Adams RH. Induction of osteogenesis by bone-targeted Notch activation. eLife 2022; 11:60183. [PMID: 35119364 PMCID: PMC8880996 DOI: 10.7554/elife.60183] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2020] [Accepted: 02/03/2022] [Indexed: 11/17/2022] Open
Abstract
Declining bone mass is associated with aging and osteoporosis, a disease characterized by progressive weakening of the skeleton and increased fracture incidence. Growth and lifelong homeostasis of bone rely on interactions between different cell types including vascular cells and mesenchymal stromal cells (MSCs). As these interactions involve Notch signaling, we have explored whether treatment with secreted Notch ligand proteins can enhance osteogenesis in adult mice. We show that a bone-targeting, high affinity version of the ligand Delta-like 4, termed Dll4(E12), induces bone formation in male mice without causing adverse effects in other organs, which are known to rely on intact Notch signaling. Due to lower bone surface and thereby reduced retention of Dll4(E12), the same approach failed to promote osteogenesis in female and ovariectomized mice but strongly enhanced trabecular bone formation in combination with parathyroid hormone. Single cell analysis of stromal cells indicates that Dll4(E12) primarily acts on MSCs and has comparably minor effects on osteoblasts, endothelial cells, or chondrocytes. We propose that activation of Notch signaling by bone-targeted fusion proteins might be therapeutically useful and can avoid detrimental effects in Notch-dependent processes in other organs.
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Affiliation(s)
- Cong Xu
- Department of Tissue Morphogenesis, Max Planck Institute for Molecular Biomedicine, Münster, Germany
| | - Van Vuong Dinh
- Department of Tissue Morphogenesis, Max Planck Institute for Molecular Biomedicine, Münster, Germany
| | - Kai Kruse
- Department of Tissue Morphogenesis, Max Planck Institute for Molecular Biomedicine, Münster, Germany
| | - Hyun-Woo Jeong
- Department of Tissue Morphogenesis, Max Planck Institute for Molecular Biomedicine, Münster, Germany
| | - Emma C Watson
- Department of Tissue Morphogenesis, Max Planck Institute for Molecular Biomedicine, Münster, Germany
| | - Susanne Adams
- Department of Tissue Morphogenesis, Max Planck Institute for Molecular Biomedicine, Münster, Germany
| | - Frank Berkenfeld
- Department of Tissue Morphogenesis, Max Planck Institute for Molecular Biomedicine, Münster, Germany
| | - Martin Stehling
- Flow Cytometry Unit, Max Planck Institute for Molecular Biomedicine, Münster, Germany
| | - Seyed Javad Rasouli
- Department of Tissue Morphogenesis, Max Planck Institute for Molecular Biomedicine, Münster, Germany
| | - Rui Fan
- Embryonic Self-Organization Research Group, Max Planck Institute for Molecular Biomedicine, Münster, Germany
| | - Rui Chen
- Embryonic Self-Organization Research Group, Max Planck Institute for Molecular Biomedicine, Münster, Germany
| | - Ivan Bedzhov
- Embryonic Self-Organization Research Group, Max Planck Institute for Molecular Biomedicine, Münster, Germany
| | - Qi Chen
- CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Guangzhou, China
| | - Katsuhiro Kato
- Department of Tissue Morphogenesis, Max Planck Institute for Molecular Biomedicine, Münster, Germany
| | - Mara Elena Pitulescu
- Tissue Morphogenesis, Max Planck Institute for Molecular Biomedicine, Münster, Germany
| | - Ralf H Adams
- Department of Tissue Morphogenesis, Max Planck Institute for Molecular Biomedicine, Münster, Germany
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