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van Mourik M, Abinzano F, Ito K. The Regulation of Pericellular Matrix Synthesis During Articular Cartilage Tissue Engineering. TISSUE ENGINEERING. PART B, REVIEWS 2025. [PMID: 40402857 DOI: 10.1089/ten.teb.2024.0316] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/24/2025]
Abstract
Articular cartilage, vital to the health and functioning of joints, remains challenging to regenerate. The pericellular matrix (PCM) is critical for transducing biophysical stimuli to the articular chondrocytes (ACs) that it envelops. Given the mechanobiological sensitivity of ACs, it is pivotal in maintaining the chondrogenic phenotype and the production of extracellular matrix (ECM) during articular cartilage tissue engineering. While the maintenance of the native PCM significantly improves the quality of neocartilage, current isolation methods are limited. A solution to this challenge is facilitating ACs to regenerate their PCM. However, the regulation of PCM synthesis remains poorly understood, hindering the development of effective tissue engineering strategies. This narrative review aims to provide a comprehensive analysis of the complex interplay between extracellular cues and intracellular pathways regulating PCM synthesis during articular cartilage tissue engineering. Our analysis reveals that mechanical cues, such as material stiffness and mechanical stimulation, are the primary regulators of PCM synthesis. Additionally, the use of scaffold-free techniques potentially affects the structuring of newly created PCM. Tuning these stimuli can significantly impact the quality of the formed PCM, ultimately influencing neocartilage quality. Furthermore, we highlight intracellular mechanisms involved in the transduction of these extracellular cues, including actin polymerization, yes-associated protein and transcriptional coactivator with PDZ-binding motif localization, and transforming growth factor beta-induced Smad signaling. Although the current literature suggests the involvement of these signaling pathways in regulating the synthesis of PCM components, we found that studies investigating these processes in ACs are lacking. Elucidating the relationships between extracellular stimuli, intracellular signaling, and the expression of PCM components could provide a framework for designing new cartilage tissue engineering approaches that facilitate proper PCM synthesis. Ultimately, this can improve ECM quality and advance articular cartilage regeneration.
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Affiliation(s)
- Marloes van Mourik
- Orthopaedic Biomechanics, Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands
| | - Florencia Abinzano
- Orthopaedic Biomechanics, Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands
| | - Keita Ito
- Orthopaedic Biomechanics, Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands
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Pérez Expósito RE, Ortega Núñez MA, Buján Varela MJ, Vega Rodríguez RM, Ortíz Chércoles AI, De La Torre Escuredo BJ. Efficacy of new active viscosupplements on the behavior of an experimental model of osteoarthritis. Rev Esp Cir Ortop Traumatol (Engl Ed) 2025; 69:150-157. [PMID: 38657788 DOI: 10.1016/j.recot.2024.04.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Accepted: 04/14/2024] [Indexed: 04/26/2024] Open
Abstract
OBJECTIVE To evaluate with an animal model of osteoarthritis (New Zealand rabbits) the effectiveness of treatment with active viscosupplements (hyaluronic acid loaded with nanoparticles (NPs) that encapsulate anti-inflammatory compounds or drugs. MATERIAL AND METHODS Experimental study composed of 5 groups of rabbits in which section of the anterior cruciate ligament and resection of the internal meniscus were performed to trigger degenerative changes and use it as a model of osteoarthritis. The groups were divided into osteoarthrosis without treatment (I), treatment with commercial hyaluronic acid (HA) (II), treatment with HA with empty nanoparticles (III), treatment with HA with nanoparticles encapsulating dexamethasone (IV) and treatment with HA with nanoparticles that encapsulate curcumin (V). In groups II to V, the infiltration of the corresponding compound was carried out spaced one week apart. Macroscopic histological analysis was performed using a scale based on the Outerbridge classification for osteoarthritis. RESULTS We observed that this osteoarthritis model is reproducible and degenerative changes similar to those found in humans are observed. The groups that were infiltrated with hyaluronic acid with curcumin-loaded nanoparticles (V), followed by the dexamethasone group (IV) presented macroscopically less fibrillation, exposure of subchondral bone and sclerosis (better score on the scale) than the control groups (I) (osteoarthritis without treatment), group (II) treated with commercial hyaluronic acid and hyaluronic acid with nanoparticles without drug (III). CONCLUSIONS The use of active viscosupplements could have an additional effect to conventional hyaluronic acid treatment due to its antioxidant and anti-inflammatory effect. The most promising group was hyaluronic acid with nanoparticles that encapsulate curcumin and the second group was the one that encapsulates dexamethasone.
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Affiliation(s)
- R E Pérez Expósito
- Servicio de Cirugía Ortopédica y Traumatología. Hospital Universitario Ramón y Cajal. Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, España.
| | | | | | - R M Vega Rodríguez
- Servicio de Cirugía Ortopédica y Traumatología. Hospital Universitario Ramón y Cajal. Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, España
| | - A I Ortíz Chércoles
- Departamento de Veterinaria U.C. Experimental Animalario Hospital Universitario Ramón y Cajal, Madrid, España
| | - B J De La Torre Escuredo
- Servicio de Cirugía Ortopédica y Traumatología. Hospital Universitario Ramón y Cajal. Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, España; Universidad de Alcalá de Henares, Madrid, España
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Pérez Expósito RE, Ortega Núñez MA, Buján Varela MJ, Vega Rodríguez RM, Ortíz Chércoles AI, De La Torre Escuredo BJ. [Translated article] Efficacy of new active viscosupplements on the behaviour of an experimental model of osteoarthritis. Rev Esp Cir Ortop Traumatol (Engl Ed) 2025; 69:T150-T157. [PMID: 39653135 DOI: 10.1016/j.recot.2024.12.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Accepted: 04/14/2024] [Indexed: 01/02/2025] Open
Abstract
OBJECTIVE To evaluate with an animal model of osteoarthritis (New Zealand rabbits) the effectiveness of treatment with active viscosupplements (hyaluronic acid loaded with nanoparticles (NPs) that encapsulate anti-inflammatory compounds or drugs. MATERIAL AND METHODS Experimental study composed of 5 groups of rabbits in which section of the anterior cruciate ligament and resection of the internal meniscus were performed to trigger degenerative changes and use it as a model of osteoarthritis. The groups were divided into osteoarthrosis without treatment (I), treatment with commercial hyaluronic acid (HA) (II), treatment with HA with empty nanoparticles (III), treatment with HA with nanoparticles encapsulating dexamethasone (IV) and treatment with HA with nanoparticles that encapsulate curcumin (V). In groups II-V, the infiltration of the corresponding compound was carried out spaced one week apart. Macroscopic histological analysis was performed using a scale based on the Outerbridge classification for osteoarthritis. RESULTS We observed that this osteoarthritis model is reproducible and degenerative changes similar to those found in humans are observed. The groups that were infiltrated with hyaluronic acid with curcumin-loaded nanoparticles (V), followed by the dexamethasone group (IV) presented macroscopically less fibrillation, exposure of subchondral bone and sclerosis (better score on the scale) than the control groups (I) (osteoarthritis without treatment), group (II) treated with commercial hyaluronic acid and hyaluronic acid with nanoparticles without drug (III). CONCLUSIONS The use of active viscosupplements could have an additional effect to conventional hyaluronic acid treatment due to its antioxidant and anti-inflammatory effect. The most promising group was hyaluronic acid with nanoparticles that encapsulate curcumin and the second group was the one that encapsulates dexamethasone.
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Affiliation(s)
- R E Pérez Expósito
- Servicio de Cirugía Ortopédica y Traumatología, Hospital Universitario Ramón y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain.
| | | | | | - R M Vega Rodríguez
- Servicio de Cirugía Ortopédica y Traumatología, Hospital Universitario Ramón y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain
| | - A I Ortíz Chércoles
- Departamento de Veterinaria U.C. Experimental Animalario Hospital Universitario Ramón y Cajal, Madrid, Spain
| | - B J De La Torre Escuredo
- Servicio de Cirugía Ortopédica y Traumatología, Hospital Universitario Ramón y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain; Universidad de Alcalá de Henares, Madrid, Spain
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Palma C, Piazza S, Visone R, Ringom R, Björklund U, Bermejo Gómez A, Rasponi M, Occhetta P. An Advanced Mechanically Active Osteoarthritis-on-Chip Model to Test Injectable Therapeutic Formulations: The SYN321 Case Study. Adv Healthc Mater 2024; 13:e2401187. [PMID: 39318108 DOI: 10.1002/adhm.202401187] [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: 03/29/2024] [Revised: 09/10/2024] [Indexed: 09/26/2024]
Abstract
Current treatments for osteoarthritis (OA) often fail to address the underlying pathophysiology and may have systemic side effects, particularly associated with long-term use of non-steroidal anti-inflammatory drugs (NSAIDs). Thus, researchers are currently directing their efforts toward innovative polymer-drug combinations, such as mixtures of hyaluronic acid viscoelastic hydrogels and NSAIDs like diclofenac, to ensure sustained release of the NSAID within the joint following intra-articular injection. However, the progress of novel injectable therapies for OA is hindered by the absence of preclinical models that accurately represent the pathology of the disease. The uBeat® MultiCompress platform is here presented as a novel approach for studying anti-OA injectable therapeutics on human mechanically-damaged OA cartilage microtissues, in a physiologically relevant environment. This platform can accommodate injectable therapeutic formulations and is successfully tested with SYN321, a novel diclofenac-sodium hyaluronate conjugate under development as a treatment for knee OA. Results indicate the platform's effectiveness in evaluating therapeutic potential, showing downregulation of inflammatory markers and reduction in matrix degradation in OA cartilage micro-tissues treated with SYN321. The uBeat® MultiCompress platform thus represents a valuable tool for OA research, offering a bridge between traditional in vitro studies and potential clinical applications, with implications for future drug discovery.
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Affiliation(s)
- Cecilia Palma
- Department of Electronics, Information and Bioengineering, Politecnico di Milano, Via Ponzio 34/5, Milan, 20133, Italy
| | - Stefano Piazza
- BiomimX Srl, Viale Decumano 41, MIND - Milano Innovation District, Milan, 20157, Italy
| | - Roberta Visone
- BiomimX Srl, Viale Decumano 41, MIND - Milano Innovation District, Milan, 20157, Italy
| | - Rune Ringom
- Recipharm OT Chemistry AB, Virdings allé 18, Uppsala, 754 50, Sweden
| | - Ulf Björklund
- UB-consulting AB, Trädgårdsgatan 7A, Uppsala, 753 09, Sweden
| | | | - Marco Rasponi
- Department of Electronics, Information and Bioengineering, Politecnico di Milano, Via Ponzio 34/5, Milan, 20133, Italy
| | - Paola Occhetta
- Department of Electronics, Information and Bioengineering, Politecnico di Milano, Via Ponzio 34/5, Milan, 20133, Italy
- BiomimX Srl, Viale Decumano 41, MIND - Milano Innovation District, Milan, 20157, Italy
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Liu X, Peng S, Pei Y, Huo Y, Zong Y, Ren J, Zhao J. Facile fabrication of chitosan/hyaluronic acid hydrogel-based wound closure material Co-loaded with gold nanoparticles and fibroblast growth factor to improve anti-microbial and healing efficiency in diabetic wound healing and nursing care. Regen Ther 2024; 26:1018-1029. [PMID: 39553541 PMCID: PMC11565426 DOI: 10.1016/j.reth.2024.10.003] [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: 08/13/2024] [Revised: 09/27/2024] [Accepted: 10/10/2024] [Indexed: 11/19/2024] Open
Abstract
Generally, diabetic wounds heal very slowly and inefficiently with an increasing risk of infections. Recent nanotechnology and biomaterial advances elaborate developed multi-functional hydrogels and nanoparticles offer promising solutions to accelerate wound healing for diabetic patients. This research work demonstrates to use of solvent diffusion method to develop hydrogel nanocomposites composed of chitosan (CS), hyaluronic acid (HA), gold (Au), and fibroblast growth factors (FGF). The biological analysis of nanocomposites exhibited enhanced wound healing efficiency by incorporating bioactive molecules like FGF and bioactive Au nanoparticles. In vitro, cell compatibility analysis (MTT assay) of prepared hydrogel nanocomposites was studied on fibroblast cell lines NIH-3T3-L1 and L929 and exhibited greater cell survival ability (>90 %), cell proliferation and migration ability, which demonstrated the suitability of nanocomposite for wound healing treatment. In vitro, anti-bacterial analyses established that FGF-Au@CS/HA has strong antibacterial effectiveness against gram-positive and gram-negative pathogens. The observation of the present research revealed that prepared FGF-Au@CS/HA hydrogel composites could be a suitable biomaterial for diabetic wound care, potentially improving its antibacterial and healing efficacies.
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Affiliation(s)
- Xin Liu
- Department of Respiratory Intensive Care Unit, Henan Provincial Key Medicine Laboratory of Nursing, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Zhengzhou, Henan, 450003, China
| | - Shengwei Peng
- Department of Respiratory Intensive Care Unit, Henan Provincial Key Medicine Laboratory of Nursing, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Zhengzhou, Henan, 450003, China
| | - Yongju Pei
- Department of Respiratory Intensive Care Unit, Henan Provincial Key Medicine Laboratory of Nursing, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Zhengzhou, Henan, 450003, China
| | - Yuanyuan Huo
- Department of Respiratory Intensive Care Unit, Henan Provincial Key Medicine Laboratory of Nursing, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Zhengzhou, Henan, 450003, China
| | - Yadi Zong
- Department of Pediatric Surgery, Henan Provincial Key Medicine Laboratory of Nursing, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Zhengzhou, Henan, 450003, China
| | - Jianwei Ren
- Department of Respiratory Intensive Care Unit, Henan Provincial Key Medicine Laboratory of Nursing, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Zhengzhou, Henan, 450003, China
| | - Jing Zhao
- Department of Respiratory Intensive Care Unit, Henan Provincial Key Medicine Laboratory of Nursing, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Zhengzhou, Henan, 450003, China
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Cui L, Pi J, Qin B, Cui T, Liu Z, Lei L, Wu S. Advanced application of carbohydrate-based micro/nanoparticles for rheumatoid arthritis. Int J Biol Macromol 2024; 269:131809. [PMID: 38677672 DOI: 10.1016/j.ijbiomac.2024.131809] [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: 12/31/2023] [Revised: 04/03/2024] [Accepted: 04/05/2024] [Indexed: 04/29/2024]
Abstract
Rheumatoid arthritis (RA) is a kind of synovitis and progressive joint destruction disease. Dysregulated immune cell activation, inflammatory cytokine overproduction, and subsequent reactive oxidative species (ROS) production contribute to the RA process. Carbohydrates, including cellulose, chitosan, alginate and dextran, are among the most abundant and important biomolecules in nature and are widely used in biomedicine. Carbohydrate-based micro/nanoparticles(M/NPs) as functional excipients have the ability to improve the bioavailability, solubility and stability of numerous drugs used in RA therapy. For on-demand therapy, smart reactive M/NPs have been developed to respond to a variety of chemical and physical stimuli, including light, temperature, enzymes, pH and ROS, alternating their physical and macroscopic properties, resulting in innovative new drug delivery systems. In particular, advanced products with targeted dextran or hyaluronic acid are exploiting multiple beneficial properties at the same time. In addition to those that respond, there are promising new derivatives in development with microenvironment and chronotherapy effects. In this review, we provide an overview of these recent developments and an outlook on how this class of agents will further shape the landscape of drug delivery for RA treatment.
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Affiliation(s)
- Linxian Cui
- Geriatric Diseases Institute of Chengdu/Cancer Prevention and Treatment Institute of Chengdu, Department of Cardiology, Chengdu Fifth People's Hospital (The Second Clinical Medical College, Affiliated Fifth People's Hospital of Chengdu University of Traditional Chinese Medicine), Chengdu, Sichuan 611130, PR China
| | - Jinkui Pi
- Core Facilities, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, PR China
| | - Boquan Qin
- Department of Orthopedic Surgery and Orthopedic Research Institute, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, PR China
| | - Ting Cui
- Department of Neurology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, PR China
| | - Zhenfei Liu
- Department of Orthopedic Surgery and Orthopedic Research Institute, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, PR China
| | - Lei Lei
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, PR China.
| | - Shizhou Wu
- Department of Orthopedic Surgery and Orthopedic Research Institute, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, PR China.
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Takada S, Nodera R, Yoshioka K. Effects of Diclofenac Etalhyaluronate (SI-613/ONO-5704) on Cartilage Degeneration in Arthritic Rats and Inflammatory Cytokine-Stimulated Human Chondrocytes. Cartilage 2024:19476035231224050. [PMID: 38317317 PMCID: PMC11569655 DOI: 10.1177/19476035231224050] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Revised: 12/08/2023] [Accepted: 12/15/2023] [Indexed: 02/07/2024] Open
Abstract
OBJECTIVE Cartilage degeneration is a key feature of osteoarthritis (OA) and rheumatoid arthritis and is thought to negatively impact patients' quality of life. Diclofenac etalhyaluronate (DEH, SI-613/ONO-5704) is a hyaluronic acid (HA) derivative chemically bound to diclofenac (DF) that has been reported to improve OA symptoms; however, its effect on cartilage degeneration remains unknown. In the present study, we investigated the chondroprotective effect of DEH in rats with collagen-induced arthritis and interleukin-1β-stimulated human chondrocytes. DESIGN Rats with collagen-induced arthritis were administered DEH and HA intra-articularly, and DF orally. Knee joint swelling, histological scores of articular cartilage, and inflammatory (Il1b) and catabolic (Mmp3 and Mmp13) gene expression in the synovial tissue and cartilage were evaluated. In vitro direct effects of DEH on matrix metalloproteinase (MMP)-3 and MMP-13 expression were examined in interleukin-1β-stimulated human chondrocytes. RESULTS In a rat model of collagen-induced arthritis, a single intra-articular dose of DEH inhibited knee joint inflammation and cartilage degeneration. Daily oral administration of DF had similar effects. Conversely, HA administered as a single intra-articular dose had no effect. Only DEH inhibited Mmp3 gene expression in the cartilage, whereas DEH and DF inhibited Mmp3 and Mmp13 mRNA expression in the synovial tissue. In interleukin-1β-stimulated human chondrocytes, DEH and HA inhibited MMP-3 and MMP-13 production, whereas DF had no effect. CONCLUSIONS In this study, we demonstrated the chondroprotective effect of DEH in rats with collagen-induced arthritis and in interleukin-1β-stimulated human chondrocytes. Thus, DEH may suppress cartilage degeneration in patients with musculoskeletal diseases, such as OA.
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Affiliation(s)
- Shuhei Takada
- Central Research Laboratory, Research & Development Division, Seikagaku Corporation, Tokyo, Japan
| | - Risa Nodera
- Central Research Laboratory, Research & Development Division, Seikagaku Corporation, Tokyo, Japan
| | - Keiji Yoshioka
- Central Research Laboratory, Research & Development Division, Seikagaku Corporation, Tokyo, Japan
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Chevalier X, Sheehan B. Predictors of Clinical Benefit with Intra-articular Hyaluronic Acid in Patients with Knee Osteoarthritis - A Narrative Review. Curr Rheumatol Rev 2024; 20:379-387. [PMID: 38243964 PMCID: PMC11275314 DOI: 10.2174/0115733971274662240108074038] [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: 09/01/2023] [Revised: 11/21/2023] [Accepted: 12/13/2023] [Indexed: 01/22/2024]
Abstract
BACKGROUND There is conflicting evidence regarding the efficacy of viscosupplementation with intra-articular hyaluronic acid injections in knee osteoarthritis. One possible explanation for the inconsistent findings on its efficacy is that only certain subpopulations of patients benefit from this therapy. OBJECTIVE The purpose of this narrative review is to succinctly summarize the existing data on the predictive factors of clinical response to intra-articular hyaluronic acid to identify the patient profile most likely to benefit from this therapy. METHODS For this narrative review, a PubMed search was conducted in January 2023, with no date limits, to identify publications reporting predictive factors of response to viscosupplementation using the following terms: hyaluronic acid OR viscosupplem* AND osteoarthritis AND knee AND predict*. Searches were limited to randomized controlled trials, systematic reviews and meta- analyses, or observational studies written in English. Other relevant references were identified by searching the references of retrieved articles. RESULTS The disease severity was found to reliably predict response to intra-articular hyaluronic acid injections; patients with less severe disease consistently had a more robust therapeutic response than those with more severe disease. Other clinical variables such as level of baseline pain did not reliably predict response. Body mass index, and possibly age, may also be independent predictors of the response. CONCLUSION A review of the existing literature suggests that patients with less severe clinical symptoms and radiological findings, who are younger, and with a lower or normal body mass index are the best candidates for intra-articular hyaluronic acid therapy.
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Affiliation(s)
- Xavier Chevalier
- Department of Rheumatology, Hôpital Henri-Mondor, Université Paris X11, Créteil, France
| | - Brendan Sheehan
- Department of Orthopaedic Surgery, Dalhousie University (Halifax), Saint John, NB, Canada
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Gianakos AL, Kennedy JG. Rethinking Cartilage Lesions of the Ankle: An Update on the Role of Biologic Adjuvants. J Am Acad Orthop Surg 2023; 31:701-707. [PMID: 37026780 DOI: 10.5435/jaaos-d-22-01042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Accepted: 03/03/2023] [Indexed: 04/08/2023] Open
Abstract
Osteochondral lesions of the talus are common injuries in the ankle joint often resulting in early-onset osteoarthritis if left untreated. The avascular nature of articular cartilage limits healing capacity; therefore, surgical strategies are typically used in the treatment of these injuries. These treatments often result in the production of fibrocartilage rather than the native hyaline cartilage, which has decreased mechanical and tribological properties. Strategies to improve the ability of fibrocartilage to be more hyaline-like and thus more mechanically robust have been widely investigated. Biologic augmentation, including concentrated bone marrow aspirate, platelet-rich plasma, hyaluronic acid, and micronized adipose tissue, has been used in the augmentation of cartilage healing, with studies demonstrating promise. This article provides an overview and update on the various biologic adjuvants used in the treatment of cartilage injuries in the ankle joint.
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Affiliation(s)
- Arianna L Gianakos
- From the Department of Orthopaedic Surgery, NYU Langone Health, New York, NY (Gianakos and Kennedy), and the Department of Orthopaedic Surgery, Yale Medicine, Orthopaedics, and Rehabilitation, New Haven, CT (Gianakos)
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Thomas J, Chopra V, Rajput S, Guha R, Chattopadhyay N, Ghosh D. Post-Implantation Stiffening by a Bioinspired, Double-Network, Self-Healing Hydrogel Facilitates Minimally Invasive Cell Delivery for Cartilage Regeneration. Biomacromolecules 2023. [PMID: 37376790 DOI: 10.1021/acs.biomac.3c00351] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/29/2023]
Abstract
Injectable hydrogels have demonstrated advantages in cartilage repair by enabling the delivery of cells through a minimally invasive approach. However, several injectable hydrogels suffer from rapid degradation and low mechanical strength. Moreover, higher mechanical stiffness in hydrogels can have a detrimental effect on post-implantation cell viability. To address these challenges, we developed an in situ forming bioinspired double network hydrogel (BDNH) that exhibits temperature-dependent stiffening after implantation. The BDNH mimics the microarchitecture of aggrecan, with hyaluronic acid-conjugated poly(N-isopropylacrylamide) providing rigidity and Schiff base crosslinked polymers serving as the ductile counterpart. BDNHs exhibited self-healing property and enhanced stiffness at physiological temperature. Excellent cell viability, long time cell proliferation, and cartilage specific matrix production were observed in the chondrocytes cultured in the BDNH hydrogel. Evidence of cartilage regeneration in a rabbit cartilage defect model using chondrocyte-laden BDNH has suggested it to be a potential candidate for cartilage tissue engineering.
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Affiliation(s)
- Jijo Thomas
- Chemical Biology Unit, Institute of Nano Science and Technology, Knowledge City, Sector 81, Mohali, Punjab 140306, India
| | - Vianni Chopra
- Chemical Biology Unit, Institute of Nano Science and Technology, Knowledge City, Sector 81, Mohali, Punjab 140306, India
| | - Swati Rajput
- Division of Endocrinology and Centre for Research in ASTHI, CSIR-Central Drug Research Institute, Council of Scientific and Industrial Research, Lucknow, Uttar Pradesh 226031, India
| | - Rajdeep Guha
- Laboratory Animal Facility, CSIR-Central Drug Research Institute, Council of Scientific and Industrial Research, Lucknow, Uttar Pradesh 226031, India
| | - Naibedya Chattopadhyay
- Division of Endocrinology and Centre for Research in ASTHI, CSIR-Central Drug Research Institute, Council of Scientific and Industrial Research, Lucknow, Uttar Pradesh 226031, India
| | - Deepa Ghosh
- Chemical Biology Unit, Institute of Nano Science and Technology, Knowledge City, Sector 81, Mohali, Punjab 140306, India
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Weitkamp JT, Benz K, Rolauffs B, Bayer A, Weuster M, Lucius R, Gülses A, Naujokat H, Wiltfang J, Lippross S, Hoffmann M, Kurz B, Behrendt P. In Vitro Comparison of 2 Clinically Applied Biomaterials for Autologous Chondrocyte Implantation: Injectable Hydrogel Versus Collagen Scaffold. Cartilage 2023; 14:220-234. [PMID: 36859785 PMCID: PMC10416195 DOI: 10.1177/19476035231154507] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Revised: 12/20/2022] [Accepted: 12/23/2022] [Indexed: 03/03/2023] Open
Abstract
OBJECTIVE In autologous chondrocyte implantation (ACI), there is no consensus about used bioscaffolds. The aim of this study was to perform an in vitro comparative analysis of 2 clinically applied biomaterials for cartilage lesion treatment. DESIGN Monolayer expanded human chondrocytes (n = 6) were embedded in a collagen scaffold (CS) and a hyaluronic acid-based hydrogel (HA). Cells were cultured in chondropermissive medium supplemented with and without interleukin-10 (IL-10) and bone morphogenetic protein-2 (BMP-2). Gene expression of chondrogenic markers (COL1A1, COL2A1, COL10A1, ACAN, SOX9) was detected via quantitative real-time-polymerase chain reaction (RT-qPCR). Biosynthesis of matrix compounds, cell viability, morphology as well as migration from surrounding native bovine cartilage into cell-free scaffolds were analyzed histologically. Adhesion of the material to adjacent cartilage was investigated by a custom-made push-out test. RESULTS The shift of COL1/2 ratio toward COL2A1 was more pronounced in HA, and cells displayed a more spherical morphology compared with CS. BMP-2 and IL-10 significantly increased COL2A1, SOX9, and ACAN expression, which was paralleled by enhanced staining of glycosaminoglycans (GAGs) and type 2 collagen in histological sections of CS and HA. COL10A1 was not significantly expressed in HA and CS. Better interfacial integration and enhanced cell invasion was observed in CS. Push-out tests using CS showed higher bonding strength to native cartilage. CONCLUSION HA-based hydrogel revealed a more chondrocyte-like phenotype but only allowed limited cell invasion, whereas CS were advantageous in terms of cellular invasion and interfacial adhesion. These differences may be clinically relevant when treating cartilaginous or osteochondral defects.
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Affiliation(s)
- Jan-Tobias Weitkamp
- Department of Oral and Maxillofacial Surgery, University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany
- Department of Anatomy, Kiel University, Kiel, Germany
| | - Karin Benz
- TETEC Tissue Engineering Technologies AG, Reutlingen, Germany
| | - Bernd Rolauffs
- G.E.R.N. Research Center for Tissue Replacement, Regeneration & Neogenesis, Department of Orthopedics and Trauma Surgery, Medical Center Albert-Ludwigs-University of Freiburg, Faculty of Medicine, Albert-Ludwigs-University of Freiburg, Freiburg, Germany
| | - Andreas Bayer
- Department of Anatomy, Kiel University, Kiel, Germany
| | - Matthias Weuster
- Clinic for Trauma Surgery, Diako Hospital Flensburg, Flensburg, Germany
| | - Ralph Lucius
- Department of Anatomy, Kiel University, Kiel, Germany
| | - Aydin Gülses
- Department of Oral and Maxillofacial Surgery, University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany
| | - Hendrik Naujokat
- Department of Oral and Maxillofacial Surgery, University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany
| | - Jörg Wiltfang
- Department of Oral and Maxillofacial Surgery, University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany
| | - Sebastian Lippross
- Department of Trauma and Orthopedic Surgery, University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany
| | - Michael Hoffmann
- Department of Trauma Surgery, Orthopedics and Sportsorthopedics, Asklepios Klinik St. Georg, Hamburg, Germany
| | - Bodo Kurz
- Department of Anatomy, Kiel University, Kiel, Germany
| | - Peter Behrendt
- Department of Anatomy, Kiel University, Kiel, Germany
- Department of Trauma Surgery, Orthopedics and Sportsorthopedics, Asklepios Klinik St. Georg, Hamburg, Germany
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12
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Seow D, Ubillus HA, Azam MT, Mercer N, Yasui Y, Hui J, Pearce CJ, Kennedy JG. Limited evidence of adjuvant biologics with bone marrow stimulation for the treatment of osteochondral lesion of the talus: a systematic review. Knee Surg Sports Traumatol Arthrosc 2022; 30:4238-4249. [PMID: 36029315 DOI: 10.1007/s00167-022-07130-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Accepted: 08/17/2022] [Indexed: 11/27/2022]
Abstract
PURPOSE To evaluate the complication rates, continuous functional outcome scores, and return to play data following bone marrow stimulation (BMS) versus biologics ± BMS for the treatment of osteochondral lesion of the talus (OLT). METHODS A systematic review was performed. The PubMed and Embase databases were searched using specific search terms and eligibility criteria according to the PRISMA guidelines. The level of evidence was assessed using published criteria by The Journal of Bone & Joint Surgery, and the quality of evidence using the Modified Coleman Methodology Score. Continuous variables were presented as mean ± standard deviation and categorical variables as frequencies (percentages). RESULTS BMS versus BMS + hyaluronic acid (HA): no complications in either treatment arm were reported. The mean American Orthopaedic Foot and Ankle Society score was 43.5 to 67.3 points and 44.0 to 72.4 points, respectively. The mean 10 mm Visual Analogue Scale pain score was 7.7 to 3.8 points and 7.5 to 2.5 points, respectively. BMS versus BMS + concentrated bone marrow aspirate (CBMA): the pooled overall complication rate was 17/64 (26.6%) versus 11/71 (15.5%), respectively (non-significant). The pool revision rate was 15/64 (23.4%) versus 6/71 (8.5%), respectively (p = 0.016). There has been a notable poor reporting of complication rates for the use of ADSC and PRP as adjuvant biological therapies to BMS for the treatment of OLT. CONCLUSION There was an overall limited comparative clinical evidence of adjuvant biologics with BMS versus BMS alone for the treatment of OLT. BMS + HA and BMS + CBMA can provide superior outcomes, albeit the currently limited evidence. Further studies are warranted to establish the true clinical superiority of the various biologics ± BMS versus BMS alone. These studies must also compare the various biologics against one another to determine, if any, the optimal biologic for OLT. Clinicians should counsel patients accordingly on these findings as required. LEVEL OF EVIDENCE Level III.
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Affiliation(s)
- Dexter Seow
- NYU Langone Health, NYU Langone Orthopedic Hospital, New York, New York, USA
- National University Health System, Singapore, Singapore
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Hugo A Ubillus
- NYU Langone Health, NYU Langone Orthopedic Hospital, New York, New York, USA
| | - Mohammad T Azam
- NYU Langone Health, NYU Langone Orthopedic Hospital, New York, New York, USA
| | - Nathaniel Mercer
- NYU Langone Health, NYU Langone Orthopedic Hospital, New York, New York, USA
| | - Youichi Yasui
- Department of Orthopaedic Surgery, School of Medicine, Teikyo University, Tokyo, Japan
| | - James Hui
- National University Health System, Singapore, Singapore
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Christopher J Pearce
- National University Health System, Singapore, Singapore
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - John G Kennedy
- NYU Langone Health, NYU Langone Orthopedic Hospital, New York, New York, USA.
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13
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MacLeod R, Chan FV, Yuan H, Ye X, Sin YJA, Vitelli TM, Cucu T, Leung A, Baljak I, Osinski S, Fu Y, Jung GID, Amar A, DeAngelis PL, Hellman U, Cowman MK. Selective isolation of hyaluronan by solid phase adsorption to silica. Anal Biochem 2022; 652:114769. [PMID: 35660507 PMCID: PMC9589902 DOI: 10.1016/j.ab.2022.114769] [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: 12/05/2021] [Revised: 04/28/2022] [Accepted: 05/27/2022] [Indexed: 11/01/2022]
Abstract
A solid phase adsorption method for selective isolation of hyaluronan (HA) from biological samples is presented. Following enzymatic degradation of protein, HA can be separated from sulfated glycosaminoglycans, other unsulfated glycosaminoglycans, nucleic acids, and proteolytic fragments by adsorption to amorphous silica at specific salt concentrations. The adsorbed HA can be released from silica using neutral and basic aqueous solutions. HA ranging in size from ∼9 kDa to MDa polymers has been purified by this method from human serum and conditioned medium of cultured cells.
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Affiliation(s)
- Rebecca MacLeod
- Department of Biomedical Engineering, Tandon School of Engineering, New York University, 433 First Avenue, 9thfloor, New York, NY, 10010, USA.
| | - Fok Vun Chan
- Echelon Biosciences Inc., 675 Arapeen Drive, Suite 302, Salt Lake City, UT, 84108, USA.
| | - Han Yuan
- Department of Chemical and Biomolecular Engineering, Tandon School of Engineering, New York University, 6 Metrotech Center, Brooklyn, NY, 11201, USA.
| | - Xin Ye
- Department of Chemical and Biomolecular Engineering, Tandon School of Engineering, New York University, 6 Metrotech Center, Brooklyn, NY, 11201, USA.
| | - Yun Jin Ashley Sin
- Department of Biomedical Engineering, Tandon School of Engineering, New York University, 433 First Avenue, 9thfloor, New York, NY, 10010, USA.
| | - Teraesa M Vitelli
- Department of Biomedical Engineering, Tandon School of Engineering, New York University, 433 First Avenue, 9thfloor, New York, NY, 10010, USA.
| | - Tudor Cucu
- Department of Chemical and Biomolecular Engineering, Tandon School of Engineering, New York University, 6 Metrotech Center, Brooklyn, NY, 11201, USA.
| | - Annie Leung
- Department of Chemical and Biomolecular Engineering, Tandon School of Engineering, New York University, 6 Metrotech Center, Brooklyn, NY, 11201, USA.
| | - Irene Baljak
- Department of Biomedical Engineering, Tandon School of Engineering, New York University, 433 First Avenue, 9thfloor, New York, NY, 10010, USA.
| | - Samantha Osinski
- Department of Chemical and Biomolecular Engineering, Tandon School of Engineering, New York University, 6 Metrotech Center, Brooklyn, NY, 11201, USA.
| | - Yuhong Fu
- Department of Chemical and Biomolecular Engineering, Tandon School of Engineering, New York University, 6 Metrotech Center, Brooklyn, NY, 11201, USA.
| | - Gyu Ik Daniel Jung
- Department of Chemical and Biomolecular Engineering, Tandon School of Engineering, New York University, 6 Metrotech Center, Brooklyn, NY, 11201, USA.
| | - Anant Amar
- Department of Chemical and Biomolecular Engineering, Tandon School of Engineering, New York University, 6 Metrotech Center, Brooklyn, NY, 11201, USA.
| | - Paul L DeAngelis
- Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, 940 Stanton L. Young Blvd., Oklahoma, OK, 73104, USA.
| | - Urban Hellman
- Department of Public Health and Clinical Medicine, Umeå University, SE-901 87, Umeå, Sweden.
| | - Mary K Cowman
- Department of Biomedical Engineering, Tandon School of Engineering, New York University, 433 First Avenue, 9thfloor, New York, NY, 10010, USA; Department of Chemical and Biomolecular Engineering, Tandon School of Engineering, New York University, 6 Metrotech Center, Brooklyn, NY, 11201, USA.
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14
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Luo W, Lin Z, Yuan Y, Wu Z, Zhong W, Liu Q. Osteopontin (OPN) alleviates the progression of osteoarthritis by promoting the anabolism of chondrocytes. Genes Dis 2022. [DOI: 10.1016/j.gendis.2022.08.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/14/2022] Open
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15
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Wang Y, Deng Q, Zheng Q, Li R, Liu B, Mo X, Zhou J, Shen J. A Composite Nanomaterial with the Ability to Regulate Oxidative Stress and Anti‐inflammatory for the Treatment of Osteoarthritis. ChemistrySelect 2022. [DOI: 10.1002/slct.202201012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Affiliation(s)
- Yi Wang
- School of Food Science and Pharmaceutical Engineering Nanjing Normal University Nanjing 210023 P. R. China
| | - Qiuping Deng
- College of Life Sciences Nanjing Normal University Nanjing 210023 P. R. China
| | - Qinghua Zheng
- School of Food Science and Pharmaceutical Engineering Nanjing Normal University Nanjing 210023 P. R. China
| | - Ruyan Li
- College of Life Sciences Nanjing Normal University Nanjing 210023 P. R. China
| | - Baoqing Liu
- College of Life Sciences Nanjing Normal University Nanjing 210023 P. R. China
| | - Xiaoli Mo
- Biology Department Clark University Worcester MA USA
| | - Jiahong Zhou
- College of Life Sciences Nanjing Normal University Nanjing 210023 P. R. China
| | - Jian Shen
- College of Chemistry and Materials Science Jiangsu Key Laboratory of Biofunctional Materials Nanjing Normal University Nanjing 210023 P. R. China
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16
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Yamamoto T, Suzuki S, Fujii T, Mima Y, Watanabe K, Matsumoto M, Nakamura M, Fujita N. Efficacy of hyaluronic acid on intervertebral disc inflammation: An in vitro study using notochordal cell lines and human disc cells. J Orthop Res 2021; 39:2197-2208. [PMID: 33251629 DOI: 10.1002/jor.24933] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Revised: 11/09/2020] [Accepted: 11/25/2020] [Indexed: 02/04/2023]
Abstract
Hyaluronic acid (HA) is widely recognized as a therapeutic target and currently used in medicine. However, HA metabolism during intervertebral disc degeneration (IVDD) has not been completely elucidated. This study aimed to evaluate the efficacy of HA on intervertebral disc (IVD) inflammation and identify the main molecules modulating HA degradation in IVDs. To assess HA function in IVD cells in vitro, we treated human disc cells and U-CH1-N cells, a notochordal nucleus pulposus cell line, with HA or hyaluronidase. Real-time reverse transcription polymerase chain reaction (RT-PCR) and Western blot analysis showed that tumor necrosis factor alpha (TNF-α)-mediated induction of the expression of TNF-α and cyclooxygenase-2 (COX2) was clearly neutralized by HA treatment, and the expression of TNF-α and COX2 was significantly induced by hyaluronidase treatment in both cell types. Additionally, Western blot analysis showed that hyaluronidase-induced phosphorylation of p38 and Erk1/2, and that TNF-α-mediated phosphorylation of p38 and Erk1/2 was clearly reduced by HA addition. In degenerating human IVD samples, immunohistochemistry for hyaluronidase showed that the expression of hyaluronidases including HYAL1, HYAL2, and cell migration-inducing protein (CEMIP) tended to increase in accordance with IVDD. In particular, HYAL1 showed statistically significant differences. In vitro study also confirmed a similar phenomenon that TNF-α treatment increased both messenger RNA and protein expression in both cell types. Our results demonstrated that HA could potentially suppress IVDD by regulating p38 and Erk1/2 pathways, and that the expression of HYAL1 was correlated with IVDD progression. These findings indicated that HYAL1 would be a potential molecular target for suppressing IVDD by controlling HA metabolism.
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Affiliation(s)
- Tatsuya Yamamoto
- Department of Orthopaedic Surgery, School of Medicine, Keio University, Tokyo, Japan
| | - Satoshi Suzuki
- Department of Orthopaedic Surgery, School of Medicine, Keio University, Tokyo, Japan
| | - Takeshi Fujii
- Department of Orthopaedic Surgery, School of Medicine, Keio University, Tokyo, Japan.,Department of Orthopaedic Surgery, Saiseikai Yokohamashi Tobu Hospital, Kanagawa, Japan
| | - Yuichiro Mima
- Department of Orthopaedic Surgery, School of Medicine, Keio University, Tokyo, Japan.,Department of Orthopaedic Surgery, Kawasaki Municipal Hospital, Kanagawa, Japan
| | - Kota Watanabe
- Department of Orthopaedic Surgery, School of Medicine, Keio University, Tokyo, Japan
| | - Morio Matsumoto
- Department of Orthopaedic Surgery, School of Medicine, Keio University, Tokyo, Japan
| | - Masaya Nakamura
- Department of Orthopaedic Surgery, School of Medicine, Keio University, Tokyo, Japan
| | - Nobuyuki Fujita
- Department of Orthopaedic Surgery, School of Medicine, Keio University, Tokyo, Japan.,Department of Orthopaedic Surgery, Fujita Health University, Toyoake, Aichi, Japan
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17
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Mahmoudian RA, Gharaie ML, Abbaszadegan MR, Alasti A, Forghanifard MM, Mansouri A, Gholamin M. Crosstalk between MMP-13, CD44, and TWIST1 and its role in regulation of EMT in patients with esophageal squamous cell carcinoma. Mol Cell Biochem 2021; 476:2465-2478. [PMID: 33604811 DOI: 10.1007/s11010-021-04089-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Accepted: 01/29/2021] [Indexed: 12/20/2022]
Abstract
Matrix metalloproteinases (MMPs) play key roles in epithelial-mesenchymal transition (EMT) for the development of cancer cell invasion and metastasis. MMP-13 is an extracellular matrix (ECM)-degrading enzyme that plays crucial roles in angiogenesis, cell cycle regulation, niche maintenance, and transforming squamous epithelial cells in various tissues. CD44, a transmembrane glycoprotein expressed on esophageal tumor cells, is required for EMT induction and invasion in esophageal squamous cell carcinoma (ESCC). The transcription factor TWIST1, as EMT and stemness marker, regulates MMPs expression and is identified as the downstream target of CD44. In this study, we aimed to investigate the probable interplay between the expression of key genes contributing to ESCC development, including MMP-13, TWIST1, and CD44 with clinical features for introducing novel diagnostic and therapeutic targets in the disease. The gene expression profiling of MMP-13, TWIST1, and CD44 was performed using quantitative real-time PCR in tumor tissues from 50 ESCC patients compared to corresponding margin non-tumoral tissues. Significant overexpression of MMP-13, CD44S, CD44V3, CD44V6, and TWIST1 were observed in 74%, 36%, 44%, 44%, and 52% of ESCC tumor samples, respectively. Overexpression of MMP-13 was associated with stage of tumor progression, metastasis, and tumor location (P < 0.05). There was a significant correlation between TWIST1 overexpression and grade (P < 0.05). Furthermore, overexpression of CD44 variants was associated with stage of tumor progression, grade, tumor invasion, and location (P < 0.05). The results indicated the significant correlation between concomitant expression of MMP-13/TWIST1, TWIST1/CD44, and CD44/MMP-13 with each other in a variety of clinicopathological traits, including depth of tumor invasion, tumor location, stage of tumor, and lymph node involvement in ESCC tissue samples (P < 0.05). Collectively, our results indicate that the TWIST1-CD44-MMP-13 axis is involved in tumor aggressiveness, proposing these genes as regulators of EMT, diagnostic markers, and therapeutic targets in ESCC.
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Affiliation(s)
| | - Maryam Lotfi Gharaie
- Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,Division of Physiology, Department of Basic Science, Faculty of Veterinary Medicine, Ferdowsi University of Mashhad, Mashhad, Iran
| | | | - Ali Alasti
- Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | | | - Atena Mansouri
- Nanotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.,Innovated Medical Research Center and Department of Immunology, Mashhad Branch, Islamic Azad University, Mashhad, Iran
| | - Mehran Gholamin
- Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran. .,Department of Laboratory Sciences, School of Paramedical Sciences, Mashhad University of Medical Sciences, P.O.Box 345-91357, Mashhad, Iran.
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18
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Li C, Cao Z, Li W, Liu R, Chen Y, Song Y, Liu G, Song Z, Liu Z, Lu C, Liu Y. A review on the wide range applications of hyaluronic acid as a promising rejuvenating biomacromolecule in the treatments of bone related diseases. Int J Biol Macromol 2020; 165:1264-1275. [PMID: 33039536 DOI: 10.1016/j.ijbiomac.2020.09.255] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Revised: 09/27/2020] [Accepted: 09/30/2020] [Indexed: 12/23/2022]
Abstract
Hyaluronic acid (HA) is a multifunctional high molecular weight polysaccharide produced by synoviocytes, fibroblasts, and chondrocytes, and is naturally found in many tissues and fluids, and more abundantly in articular cartilage and synovial fluid. Naturally occurring HA is thought to participate in many biological processes, such as regulation of cell adhesion and cell motility, manipulation of cell differentiation and proliferation, and providing mechanical properties to tissues (Girish and Kemparaju, 2007). Due to its excellent physicochemical properties such as high viscosity, elasticity, biodegradability, biocompatibility, nontoxicity, and nonimmunogenicity, HA based formulations have a wide range of applications and serves as a promising rejuvenating biomacromolecule in biomedical applications. In recent decades, HA is currently a popular topic, and has been widely used in bone related diseases for its remarkable efficacy in articular cartilage lubrication, analgesia, anti-inflammation, immunomodulatory, chondroprotection, anti-cancer and etc. Moreover, the safety and tolerability of HA based formulations have also been well-documented for treatment of various types of bone related diseases (Chen et al., 2018). This review gives a deep understanding on the special benefits and provides a mechanism-based rationale for the use of HA in bone related diseases conditions with special reference to osteoarthritis (OA), rheumatoid arthritis (RA), bone metastatic cancers.
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Affiliation(s)
- Chenxi Li
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100102, China
| | - Zhiwen Cao
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100102, China.
| | - Wen Li
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100102, China
| | - Rui Liu
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100102, China
| | - Youwen Chen
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100102, China
| | - Yurong Song
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100102, China
| | - Guangzhi Liu
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100102, China
| | - Zhiqian Song
- Institution of Basic Theory, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Zhenli Liu
- Institution of Basic Theory, China Academy of Chinese Medical Sciences, Beijing 100700, China.
| | - Cheng Lu
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing 100700, China.
| | - Yuanyan Liu
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100102, China.
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19
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Nishida Y, Kano K, Nobuoka Y, Seo T. Sustained-release diclofenac conjugated to hyaluronate (diclofenac etalhyaluronate) for knee osteoarthritis: a randomized phase 2 study. Rheumatology (Oxford) 2020; 60:1435-1444. [PMID: 33006602 PMCID: PMC7937021 DOI: 10.1093/rheumatology/keaa605] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Revised: 08/17/2020] [Indexed: 01/22/2023] Open
Abstract
Objective To evaluate the efficacy and safety of diclofenac etalhyaluronate (DF-HA) (ONO-5704/SI-613), a novel DF-conjugated hyaluronate, in patients with knee OA in Japan. Methods In this randomized, double-blind, placebo-controlled phase 2 study, patients were randomly assigned (1:1) to receive either 30 mg of DF-HA or placebo intra-articularly at weeks 0, 4 and 8 and were followed up for 24 weeks. The primary outcomes were changes from baseline in the WOMAC pain subscores, 50-foot walk test pain score and daily pain score. The secondary outcomes were the WOMAC physical function subscores, patient global assessment, responder rate and safety outcome. Results Overall, 176 patients received the investigational drugs (87 received DF-HA and 89 received placebo). The mean changes in the WOMAC pain subscores and daily pain score from baseline over 12 weeks after the first injection were significantly higher in the DF-HA than placebo group; the mean difference was −7.0 mm [95% CI, −12.7, −1.2; P =0.018] and −0.61 (95% CI, −1.06, −0.16; P =0.008), respectively. The difference in the 50-foot walk test pain score was −5.0 mm (95% CI, −10.3, 0.3; P =0.065). Improvement of pain by DF-HA was observed at week 1 and maintained from week 12 to week 24. Significantly greater improvements in the secondary outcomes were also observed with DF-HA than with placebo. No clinically significant adverse events occurred. Conclusion DF-HA reduced pain in patients with knee OA without major safety concerns. Trial registration UMIN Clinical Trials Registry, https://www.umin.ac.jp/ctr/index.htm, UMIN000015858
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Affiliation(s)
- Yoshihiro Nishida
- Department of Rehabilitation, Orthopaedic Surgery, Nagoya University Hospital, Nagoya, Japan
| | - Kazuyuki Kano
- Research & Development Division, Clinical Development Department, Seikagaku Corporation, Tokyo, Japan
| | - Yuji Nobuoka
- Research & Development Division, Clinical Development Department, Seikagaku Corporation, Tokyo, Japan
| | - Takayuki Seo
- Research & Development Division, Clinical Development Department, Seikagaku Corporation, Tokyo, Japan
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20
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Kanchanathepsak T, Pichyangkul P, Suppaphol S, Watcharananan I, Tuntiyatorn P, Tawonsawatruk T. Efficacy Comparison of Hyaluronic Acid and Corticosteroid Injection in Treatment of Trigger Digits: A Randomized Controlled Trial. J Hand Surg Asian Pac Vol 2020; 25:76-81. [PMID: 32000598 DOI: 10.1142/s2424835520500101] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Background: Although the current nonsurgical treatment for trigger digits is corticosteroid (CS) injection, it often comes with adverse effects that may cause some limitations. Currently, Hyaluronic acid (HA) has been successfully used in tendinopathy and may be used in stenosing tenosynovitis. The aim of this study is to compare the efficacy of ultrasound-guided injection between the HA and CS in trigger digits treatment. Methods: Double-blind randomized controlled trial was conducted. Fifty patients with 66 trigger digits were randomly assigned into an intervention group (1 ml of low-molecular weight HA) and a control group (1 ml of 10mg/ml triamcinolone acetate). The ultrasound-guided injection and local anesthesia (0.5 ml of 1% lidocaine without adrenaline) were used. The Quinnell grading, Visual Analog Scale (VAS) score of pain, Disabilities of the Arm, Shoulder and Hand (DASH) score and complications were collected at 1-, 3-and 6-month follow-up. Results: The mean age of HA group (33 digits) and CS group (33 digits) were 58.3 years and 54.7 years respectively. Nine patients were loss of follow-up (7 in HA group and 2 in CS group). The Quinnell grades have shown an improvement in both group. The CS group had a significant better improvement at 1-month (p-value < 0.001) and there was no significant difference at 3-and 6-month follow-up between the two groups. The median of VAS and DASH score were significantly improved by time in both groups (p-value < 0.01). The CS group showed a better significant improvement in early period of follow-up (p-value < 0.05). However, there was no significant difference between the two groups in the last follow-up. Conclusions: HA and CS injection has a comparable therapeutic effect in treatment of trigger digits. However, CS injection has higher efficacy of pain and inflammation reduction in the early phase of the disease.
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Affiliation(s)
- Thepparat Kanchanathepsak
- Hand and Microsurgery Unit, Department of Orthopaedics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Picharn Pichyangkul
- Hand and Microsurgery Unit, Department of Orthopaedics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Sorasak Suppaphol
- Hand and Microsurgery Unit, Department of Orthopaedics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Ittirat Watcharananan
- Hand and Microsurgery Unit, Department of Orthopaedics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Panithan Tuntiyatorn
- Hand and Microsurgery Unit, Chakri Naruebodindra Medical Institute, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Samutprakan, Thailand
| | - Tulyapruek Tawonsawatruk
- Hand and Microsurgery Unit, Department of Orthopaedics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
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21
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Filová E, Tonar Z, Lukášová V, Buzgo M, Litvinec A, Rampichová M, Beznoska J, Plencner M, Staffa A, Daňková J, Soural M, Chvojka J, Malečková A, Králíčková M, Amler E. Hydrogel Containing Anti-CD44-Labeled Microparticles, Guide Bone Tissue Formation in Osteochondral Defects in Rabbits. NANOMATERIALS (BASEL, SWITZERLAND) 2020; 10:E1504. [PMID: 32751860 PMCID: PMC7466545 DOI: 10.3390/nano10081504] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Revised: 07/23/2020] [Accepted: 07/28/2020] [Indexed: 12/14/2022]
Abstract
Hydrogels are suitable for osteochondral defect regeneration as they mimic the viscoelastic environment of cartilage. However, their biomechanical properties are not sufficient to withstand high mechanical forces. Therefore, we have prepared electrospun poly-ε-caprolactone-chitosan (PCL-chit) and poly(ethylene oxide)-chitosan (PEO-chit) nanofibers, and FTIR analysis confirmed successful blending of chitosan with other polymers. The biocompatibility of PCL-chit and PEO-chit scaffolds was tested; fibrochondrocytes and chondrocytes seeded on PCL-chit showed superior metabolic activity. The PCL-chit nanofibers were cryogenically grinded into microparticles (mean size of about 500 µm) and further modified by polyethylene glycol-biotin in order to bind the anti-CD44 antibody, a glycoprotein interacting with hyaluronic acid (PCL-chit-PEGb-antiCD44). The PCL-chit or PCL-chit-PEGb-antiCD44 microparticles were mixed with a composite gel (collagen/fibrin/platelet rich plasma) to improve its biomechanical properties. The storage modulus was higher in the composite gel with microparticles compared to fibrin. The Eloss of the composite gel and fibrin was higher than that of the composite gel with microparticles. The composite gel either with or without microparticles was further tested in vivo in a model of osteochondral defects in rabbits. PCL-chit-PEGb-antiCD44 significantly enhanced osteogenic regeneration, mainly by desmogenous ossification, but decreased chondrogenic differentiation in the defects. PCL-chit-PEGb showed a more homogeneous distribution of hyaline cartilage and enhanced hyaline cartilage differentiation.
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Affiliation(s)
- Eva Filová
- Department of Tissue Engineering, Institute of Experimental Medicine of the Czech Academy of Science, Videnska 1083, 142 20 Prague 4, Czech Republic; (E.F.); (M.B.); (A.L.); (M.R.); (M.P.); (A.S.); (J.D.); (E.A.)
- Institute of Biophysics, 2nd Faculty of Medicine, Charles University, V Uvalu 84, 150 06 Prague 5, Czech Republic
| | - Zbyněk Tonar
- Institute of Histology and Embryology and Biomedical Center, Faculty of Medicine in Pilsen, Charles University in Prague, Husova 3, 305 06 Pilsen, Czech Republic; (Z.T.); (A.M.); (M.K.)
| | - Věra Lukášová
- Department of Tissue Engineering, Institute of Experimental Medicine of the Czech Academy of Science, Videnska 1083, 142 20 Prague 4, Czech Republic; (E.F.); (M.B.); (A.L.); (M.R.); (M.P.); (A.S.); (J.D.); (E.A.)
| | - Matěj Buzgo
- Department of Tissue Engineering, Institute of Experimental Medicine of the Czech Academy of Science, Videnska 1083, 142 20 Prague 4, Czech Republic; (E.F.); (M.B.); (A.L.); (M.R.); (M.P.); (A.S.); (J.D.); (E.A.)
- Institute of Biophysics, 2nd Faculty of Medicine, Charles University, V Uvalu 84, 150 06 Prague 5, Czech Republic
| | - Andrej Litvinec
- Department of Tissue Engineering, Institute of Experimental Medicine of the Czech Academy of Science, Videnska 1083, 142 20 Prague 4, Czech Republic; (E.F.); (M.B.); (A.L.); (M.R.); (M.P.); (A.S.); (J.D.); (E.A.)
| | - Michala Rampichová
- Department of Tissue Engineering, Institute of Experimental Medicine of the Czech Academy of Science, Videnska 1083, 142 20 Prague 4, Czech Republic; (E.F.); (M.B.); (A.L.); (M.R.); (M.P.); (A.S.); (J.D.); (E.A.)
| | - Jiří Beznoska
- Hospital of Rudolfa and Stefanie, a. s., Máchova 400, 256 30 Benešov, Czech Republic;
| | - Martin Plencner
- Department of Tissue Engineering, Institute of Experimental Medicine of the Czech Academy of Science, Videnska 1083, 142 20 Prague 4, Czech Republic; (E.F.); (M.B.); (A.L.); (M.R.); (M.P.); (A.S.); (J.D.); (E.A.)
| | - Andrea Staffa
- Department of Tissue Engineering, Institute of Experimental Medicine of the Czech Academy of Science, Videnska 1083, 142 20 Prague 4, Czech Republic; (E.F.); (M.B.); (A.L.); (M.R.); (M.P.); (A.S.); (J.D.); (E.A.)
| | - Jana Daňková
- Department of Tissue Engineering, Institute of Experimental Medicine of the Czech Academy of Science, Videnska 1083, 142 20 Prague 4, Czech Republic; (E.F.); (M.B.); (A.L.); (M.R.); (M.P.); (A.S.); (J.D.); (E.A.)
| | - Miroslav Soural
- Department of Organic Chemistry, Faculty of Science, Palacky University, 17. listopadu 12, 771 46 Olomouc, Czech Republic;
| | - Jiří Chvojka
- Faculty of Textile Engineering, Technical University of Liberec, Studentská 2, 461 17 Liberec, Czech Republic;
| | - Anna Malečková
- Institute of Histology and Embryology and Biomedical Center, Faculty of Medicine in Pilsen, Charles University in Prague, Husova 3, 305 06 Pilsen, Czech Republic; (Z.T.); (A.M.); (M.K.)
| | - Milena Králíčková
- Institute of Histology and Embryology and Biomedical Center, Faculty of Medicine in Pilsen, Charles University in Prague, Husova 3, 305 06 Pilsen, Czech Republic; (Z.T.); (A.M.); (M.K.)
| | - Evžen Amler
- Department of Tissue Engineering, Institute of Experimental Medicine of the Czech Academy of Science, Videnska 1083, 142 20 Prague 4, Czech Republic; (E.F.); (M.B.); (A.L.); (M.R.); (M.P.); (A.S.); (J.D.); (E.A.)
- Institute of Biophysics, 2nd Faculty of Medicine, Charles University, V Uvalu 84, 150 06 Prague 5, Czech Republic
- Student Science s.r.o., Národních Hrdinů 279, Dolní Počernice, 190 12 Prague, Czech Republic
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Liu Q, Zeng H, Yuan Y, Wang Z, Wu Z, Luo W. Osteopontin inhibits osteoarthritis progression via the OPN/CD44/PI3K signal axis. Genes Dis 2020; 9:128-139. [PMID: 35005113 PMCID: PMC8720673 DOI: 10.1016/j.gendis.2020.06.006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Revised: 05/26/2020] [Accepted: 06/12/2020] [Indexed: 12/23/2022] Open
Abstract
Chondrocyte degeneration and extracellular matrix component loss are the primary causes of osteoarthritis (OA). OA can be treated by inhibiting chondrocyte degeneration and increasing extracellular matrix component secretion. Osteopontin (OPN), a multifunctional protein, has gained immense attention with regard to its involvement in OA. This study aimed to explore the therapeutic value and mechanism of action of OPN in OA treatment. Results of the histomorphological analysis revealed a worn-off OA cartilage tissue surface, cartilage matrix layer deterioration, and calcium salt deposition. Compared to that in normal chondrocytes, in OA chondrocytes, the OPN, CD44, and PI3K protein and mRNA expression was upregulated. Further, siOPN, rhOPN, and rhOPN plus LS-C179404 interfered with OA chondrocytes. As verified in mice, OPN directly inhibited the expression level of PI3K in OA chondrocytes by binding with CD44. Morphological analysis of the knee joints demonstrated that OPN effectively inhibited OA progression via the OPN/CD44/PI3K signal axis. In conclusion, OPN activates intracellular PI3K signaling molecules by binding to CD44 on the cell surface to cause downstream cascading effects, thereby delaying chondrocyte degeneration and reducing cartilage matrix component loss; therefore, OPN is a potential therapeutic agent for OA.
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Affiliation(s)
- Qing Liu
- Department of Orthopaedics, Xiangya Hospital, Central South University, 87th Xiangya Road, Changsha, Hunan 410008, PR China.,Department of Spine Surgery, The Second Xiangya Hospital, Central South University, 139th Renmin Middle Road, Changsha, Hunan 410011, PR China.,Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Hao Zeng
- Department of Orthopaedics, Xiangya Hospital, Central South University, 87th Xiangya Road, Changsha, Hunan 410008, PR China
| | - Yuhao Yuan
- Department of Orthopaedics, Xiangya Hospital, Central South University, 87th Xiangya Road, Changsha, Hunan 410008, PR China
| | - Zhiwei Wang
- Department of Orthopaedics, Xiangya Hospital, Central South University, 87th Xiangya Road, Changsha, Hunan 410008, PR China
| | - Ziyi Wu
- Department of Orthopaedics, Xiangya Hospital, Central South University, 87th Xiangya Road, Changsha, Hunan 410008, PR China
| | - Wei Luo
- Department of Orthopaedics, Xiangya Hospital, Central South University, 87th Xiangya Road, Changsha, Hunan 410008, PR China
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Cowman MK, Shortt C, Arora S, Fu Y, Villavieja J, Rathore J, Huang X, Rakshit T, Jung GI, Kirsch T. Role of Hyaluronan in Inflammatory Effects on Human Articular Chondrocytes. Inflammation 2020; 42:1808-1820. [PMID: 31243649 PMCID: PMC6719336 DOI: 10.1007/s10753-019-01043-9] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Hyaluronan (HA) fragments have been proposed to elicit defensive or pro-inflammatory responses in many cell types. For articular chondrocytes in an inflammatory environment, studies have failed to reach consensus on the endogenous production or effects of added HA fragments. The present study was undertaken to resolve this discrepancy. Cultured primary human articular chondrocytes were exposed to the inflammatory cytokine IL-1β, and then tested for changes in HA content/size in conditioned medium, and for the expression of genes important in HA binding/signaling or metabolism, and in other catabolic/anabolic responses. Changes in gene expression caused by enzymatic degradation of endogenous HA, or addition of exogenous HA fragments, were examined. IL-1β increased the mRNA levels for HA synthases HAS2/HAS3 and for the HA-binding proteins CD44 and TSG-6. mRNA levels for TLR4 and RHAMM were very low and were little affected by IL-1β. mRNA levels for catabolic markers were increased, while type II collagen (α1(II)) and aggrecan were decreased. HA concentration in the conditioned medium was increased, but the HA was not degraded. Treatment with recombinant hyaluronidase or addition of low endotoxin HA fragments did not elicit pro-inflammatory responses. Our findings showed that HA fragments were not produced by IL-1β-stimulated human articular chondrocytes in the absence of other sources of reactive oxygen or nitrogen species, and that exogenous HA fragments from oligosaccharides up to about 40 kDa in molecular mass were not pro-inflammatory agents for human articular chondrocytes, probably due to low expression of TLR4 and RHAMM in these cells.
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Affiliation(s)
- Mary K Cowman
- Department of Biomedical Engineering, New York University Tandon School of Engineering, 433 First Avenue, room 910, New York, NY, 10010, USA. .,Musculoskeletal Research Center, Department of Orthopaedic Surgery, New York University School of Medicine, New York, NY, USA. .,Department of Chemical and Biomolecular Engineering, New York University Tandon School of Engineering, New York, NY, USA.
| | - Claire Shortt
- Musculoskeletal Research Center, Department of Orthopaedic Surgery, New York University School of Medicine, New York, NY, USA
| | - Shivani Arora
- Department of Chemical and Biomolecular Engineering, New York University Tandon School of Engineering, New York, NY, USA
| | - Yuhong Fu
- Department of Chemical and Biomolecular Engineering, New York University Tandon School of Engineering, New York, NY, USA
| | - Jemma Villavieja
- Department of Chemical and Biomolecular Engineering, New York University Tandon School of Engineering, New York, NY, USA
| | - Jai Rathore
- Department of Chemical and Biomolecular Engineering, New York University Tandon School of Engineering, New York, NY, USA
| | - Xiayun Huang
- Department of Chemical and Biomolecular Engineering, New York University Tandon School of Engineering, New York, NY, USA
| | - Tatini Rakshit
- Department of Chemical and Biomolecular Engineering, New York University Tandon School of Engineering, New York, NY, USA
| | - Gyu Ik Jung
- Department of Chemical and Biomolecular Engineering, New York University Tandon School of Engineering, New York, NY, USA
| | - Thorsten Kirsch
- Department of Biomedical Engineering, New York University Tandon School of Engineering, 433 First Avenue, room 910, New York, NY, 10010, USA.,Musculoskeletal Research Center, Department of Orthopaedic Surgery, New York University School of Medicine, New York, NY, USA
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Tseng CC, Chen YJ, Chang WA, Tsai WC, Ou TT, Wu CC, Sung WY, Yen JH, Kuo PL. Dual Role of Chondrocytes in Rheumatoid Arthritis: The Chicken and the Egg. Int J Mol Sci 2020; 21:E1071. [PMID: 32041125 PMCID: PMC7038065 DOI: 10.3390/ijms21031071] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2020] [Revised: 02/04/2020] [Accepted: 02/04/2020] [Indexed: 12/22/2022] Open
Abstract
Rheumatoid arthritis (RA) is one of the inflammatory joint diseases that display features of articular cartilage destruction. The underlying disturbance results from immune dysregulation that directly and indirectly influence chondrocyte physiology. In the last years, significant evidence inferred from studies in vitro and in the animal model offered a more holistic vision of chondrocytes in RA. Chondrocytes, despite being one of injured cells in RA, also undergo molecular alterations to actively participate in inflammation and matrix destruction in the human rheumatoid joint. This review covers current knowledge about the specific cellular and biochemical mechanisms that account for the chondrocyte signatures of RA and its potential applications for diagnosis and prognosis in RA.
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Affiliation(s)
- Chia-Chun Tseng
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (C.-C.T.); (Y.-J.C.); (W.-A.C.)
- Division of Rheumatology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 80756, Taiwan; (W.-C.T.); (T.-T.O.); (C.-C.W.); (W.-Y.S.)
| | - Yi-Jen Chen
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (C.-C.T.); (Y.-J.C.); (W.-A.C.)
- Department of Physical Medicine and Rehabilitation, Kaohsiung Medical University Hospital, Kaohsiung 80756, Taiwan
- School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Wei-An Chang
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (C.-C.T.); (Y.-J.C.); (W.-A.C.)
- School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Division of Pulmonary and Critical Care Medicine, Kaohsiung Medical University Hospital, Kaohsiung 80756, Taiwan
| | - Wen-Chan Tsai
- Division of Rheumatology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 80756, Taiwan; (W.-C.T.); (T.-T.O.); (C.-C.W.); (W.-Y.S.)
| | - Tsan-Teng Ou
- Division of Rheumatology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 80756, Taiwan; (W.-C.T.); (T.-T.O.); (C.-C.W.); (W.-Y.S.)
| | - Cheng-Chin Wu
- Division of Rheumatology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 80756, Taiwan; (W.-C.T.); (T.-T.O.); (C.-C.W.); (W.-Y.S.)
| | - Wan-Yu Sung
- Division of Rheumatology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 80756, Taiwan; (W.-C.T.); (T.-T.O.); (C.-C.W.); (W.-Y.S.)
| | - Jeng-Hsien Yen
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (C.-C.T.); (Y.-J.C.); (W.-A.C.)
- Division of Rheumatology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 80756, Taiwan; (W.-C.T.); (T.-T.O.); (C.-C.W.); (W.-Y.S.)
| | - Po-Lin Kuo
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (C.-C.T.); (Y.-J.C.); (W.-A.C.)
- Institute of Biomedical Science, National Sun Yat-Sen University, Kaohsiung 80424, Taiwan
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25
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Shortt C, Luyt LG, Turley EA, Cowman MK, Kirsch T. A Hyaluronan-binding Peptide (P15-1) Reduces Inflammatory and Catabolic Events in IL-1β-treated Human Articular Chondrocytes. Sci Rep 2020; 10:1441. [PMID: 31996703 PMCID: PMC6989647 DOI: 10.1038/s41598-020-57586-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2019] [Accepted: 01/03/2020] [Indexed: 01/01/2023] Open
Abstract
Inflammation plays a critical role in osteoarthritis (OA). It stimulates catabolic events in articular chondrocytes and prevents chondrogenic precursor cells from repairing cartilage lesions, leading to accelerated cartilage degradation. Therefore, the identification of novel factors that reduce catabolic events in chondrocytes and enhances chondrogenic differentiation of precursor cells in an inflammatory environment may provide novel therapeutic strategies for the treatment of OA. The goal of this study was to determine whether a hyaluronan (HA)-binding peptide (P15-1), via interacting with high molecular weight (HMW)HA can enhance the anti-inflammatory properties of HMWHA and decrease catabolic events in interleukin-1beta (IL-1β)-treated human articular chondrocytes. Treatment with P15-1 decreased catabolic events and stimulated anabolic events in articular chondrocytes cultured in an inflammatory environment. P15-1 pre-mixed with HMWHA was more effective in inhibiting catabolic events and stimulating anabolic events than P15-1 or HMWHA alone. Our findings suggest that P15-1 together with HMWHA inhibits catabolic events in articular chondrocytes via the inhibition of p38 mitogen-activated protein kinases (MAPK) and increasing the thickness of the pericellular matrix (PCM) around chondrocytes thereby decreasing catabolic signaling. Finally, conditioned medium from IL-1β and P15-1-treated human articular chondrocytes was less inhibitory for chondrogenic differentiation of precursor cells than conditioned medium from chondrocytes treated with IL-1β alone. In conclusion, P15-1 is proposed to function synergistically with HMWHA to enhance the protective microenvironment for chondrocytes and mesenchymal stem cells during inflammation and regeneration.
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Affiliation(s)
- Claire Shortt
- Musculoskeletal Research Center, Department of Orthopaedic Surgery, New York University School of Medicine, New York, NY, USA
- FoodMarble Digestive Health, Dublin, 2, Ireland
| | - Leonard G Luyt
- The University of Western Ontario, London, ON, Canada
- London Regional Cancer Program, Lawson Health Research Institute, London, ON, Canada
| | - Eva A Turley
- The University of Western Ontario, London, ON, Canada
- London Regional Cancer Program, Lawson Health Research Institute, London, ON, Canada
| | - Mary K Cowman
- Musculoskeletal Research Center, Department of Orthopaedic Surgery, New York University School of Medicine, New York, NY, USA
- Department of Biomedical Engineering, New York University Tandon School of Engineering, New York, NY, USA
| | - Thorsten Kirsch
- Musculoskeletal Research Center, Department of Orthopaedic Surgery, New York University School of Medicine, New York, NY, USA.
- Department of Biomedical Engineering, New York University Tandon School of Engineering, New York, NY, USA.
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26
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Gupta RC, Lall R, Srivastava A, Sinha A. Hyaluronic Acid: Molecular Mechanisms and Therapeutic Trajectory. Front Vet Sci 2019; 6:192. [PMID: 31294035 PMCID: PMC6603175 DOI: 10.3389/fvets.2019.00192] [Citation(s) in RCA: 399] [Impact Index Per Article: 66.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2019] [Accepted: 05/30/2019] [Indexed: 01/06/2023] Open
Abstract
Hyaluronic acid (also known as hyaluronan or hyaluronate) is naturally found in many tissues and fluids, but more abundantly in articular cartilage and synovial fluid (SF). Hyaluronic acid (HA) content varies widely in different joints and species. HA is a non-sulfated, naturally occurring non-protein glycosaminoglycan (GAG), with distinct physico-chemical properties, produced by synoviocytes, fibroblasts, and chondrocytes. HA has an important role in the biomechanics of normal SF, where it is partially responsible for lubrication and viscoelasticity of the SF. The concentration of HA and its molecular weight (MW) decline as osteoarthritis (OA) progresses with aging. For that reason, HA has been used for more than four decades in the treatment of OA in dogs, horses and humans. HA produces anti-arthritic effects via multiple mechanisms involving receptors, enzymes and other metabolic pathways. HA is also used in the treatment of ophthalmic, dermal, burns, wound repair, and other health conditions. The MW of HA appears to play a critical role in the formulation of the products used in the treatment of diseases. This review provides a mechanism-based rationale for the use of HA in some disease conditions with special reference to OA.
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Affiliation(s)
- Ramesh C Gupta
- Toxicology Department, Breathitt Veterinary Center, Murray State University, Hopkinsville, KY, United States
| | - Rajiv Lall
- Vets Plus, Inc., Menomonie, WI, United States
| | | | - Anita Sinha
- Vets Plus, Inc., Menomonie, WI, United States
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27
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Hayes AJ, Melrose J. Glycosaminoglycan and Proteoglycan Biotherapeutics in Articular Cartilage Protection and Repair Strategies: Novel Approaches to Visco‐supplementation in Orthobiologics. ADVANCED THERAPEUTICS 2019. [DOI: 10.1002/adtp.201900034] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Affiliation(s)
- Anthony J. Hayes
- Bioimaging Research HubCardiff School of BiosciencesCardiff University Cardiff CF10 3AX Wales UK
| | - James Melrose
- Graduate School of Biomedical EngineeringUNSW Sydney Sydney NSW 2052 Australia
- Raymond Purves Bone and Joint Research LaboratoriesKolling Institute of Medical ResearchRoyal North Shore Hospital and The Faculty of Medicine and HealthUniversity of Sydney St. Leonards NSW 2065 Australia
- Sydney Medical SchoolNorthernRoyal North Shore HospitalSydney University St. Leonards NSW 2065 Australia
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28
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Kongdang P, Jaitham R, Thonghoi S, Kuensaen C, Pradit W, Ongchai S. Ethanolic extract of Kaempferia parviflora interrupts the mechanisms-associated rheumatoid arthritis in SW982 culture model via p38/STAT1 and STAT3 pathways. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2019; 59:152755. [PMID: 31005814 DOI: 10.1016/j.phymed.2018.11.015] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/18/2018] [Revised: 10/17/2018] [Accepted: 11/13/2018] [Indexed: 06/09/2023]
Abstract
BACKGROUND Kaempferia parviflora Wall. ex Baker (KP) has long been used in traditional medicine to treat various diseases because active compounds in rhizome extracts are important anti-inflammatory agents. PURPOSE This study aims to investigate the effects of an ethanolic extract of KP on the molecular mechanisms associated with rheumatoid arthritis (RA), which was induced by a combination of proinflammatory cytokines (IL-1β or TNF-α with IL-17A) in a human synovial sarcoma cell line (SW982) culture model. METHODS SW982 cells pretreated with cytokines were incubated with KP extract at 3-30 µg/ml, or three major compounds of KP (5,7-dimethoxyflavone, 5,7,4'-trimethoxyflavone, and 3,5,7,3',4'-pentamethoxyflavone) for up to 72 h. Dexamethasone was used as positive control. RA-associated genes and inflammatory products were measured in parallel with cell death genes. Apoptosis by flow cytometry and migration assay were also analyzed. Western blotting was used to examine the effects on intracellular signaling mechanisms. RESULTS KP extract markedly reduced the expression of genes and levels of proinflammatory cytokines, inflammatory mediators, and matrix-degraded enzymes, but neither induced apoptosis nor altered the cell cycle. Its major constituents differently exerted suppressive effects on inflammatory genes. The KP extract downregulated the expression of genes associated with autophagosome and necroptosome formations. The extract also inhibited cell migration, reduced the mRNA expression of cadherin-11, and selectively reduced the phosphorylation of p38 MAPK, STAT1, and STAT3 signaling molecules, but did not interfere with the NF-κB pathway. CONCLUSION These results suggest that the anti-arthritic potential of KP extract results from anti-inflammation and anti-migration via the suppression of the cytokines-induced p38/STAT1 and STAT3 pathways.
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Affiliation(s)
- Patiwat Kongdang
- Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand; Graduate School, Chiang Mai University, Chiang Mai, Thailand
| | - Rungnaree Jaitham
- Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Supitcha Thonghoi
- Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Chakkrapong Kuensaen
- Department of Biology, Faculty of Science, Chiang Mai University, Chiang Mai, Thailand
| | - Waranee Pradit
- Science and Technology Research Institute, Chiang Mai University, Chiang Mai, Thailand
| | - Siriwan Ongchai
- Thailand Excellence Center for Tissue Engineering and Stem Cells, Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.
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Murakami T, Otsuki S, Okamoto Y, Nakagawa K, Wakama H, Okuno N, Neo M. Hyaluronic acid promotes proliferation and migration of human meniscus cells via a CD44-dependent mechanism. Connect Tissue Res 2019; 60:117-127. [PMID: 29658360 DOI: 10.1080/03008207.2018.1465053] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
PURPOSE Treatment of meniscal injury is important for osteoarthritis (OA) prevention. Meniscus cells are divided between inner and outer cells, which have different characteristics and vascularity. We evaluated the effects of hyaluronic acid (HA) on the proliferation and migration of human inner and outer meniscus cells, and investigated the underlying healing mechanisms. MATERIALS AND METHODS Lateral menisci from 18 patients who underwent total knee arthroplasty were used. Meniscus cells were harvested from the outer and inner menisci and evaluated using migration and proliferation assays after treatment with HA or chondroitin sulfate (CS). The effects of HA on prostaglandin E2 (PGE2)-induced apoptosis and gene expression were evaluated. RESULTS Cell migration and proliferation were increased by HA in a concentration-dependent manner, in both inner and outer meniscus cells. PGE2-induced apoptosis and caspase-3/7 activity were suppressed by HA in both inner and outer meniscus cells, and these effects were blocked by an anti-CD44 antibody. COL2A1 and ACAN mRNA levels were upregulated following HA treatment of inner meniscus cells. MMP13 mRNA was downregulated following CS stimulation of both inner and outer meniscus cells. These results suggest that CS treatment suppresses the inflammatory reaction rather than providing meniscal restoration. The phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways were activated by HA in both types of meniscus cells; these effects were blocked by treatment with an anti-CD44 antibody. CONCLUSIONS HA promoted human meniscus regeneration by inhibiting apoptosis, promoting cell migration, and accelerating cell proliferation, potentially through the PI3K/MAPK pathway via the CD44 receptor.
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Affiliation(s)
| | - Shuhei Otsuki
- a Orthopedic Surgery , Osaka Medical College , Osaka , Japan
| | | | - Kosuke Nakagawa
- a Orthopedic Surgery , Osaka Medical College , Osaka , Japan
| | - Hitoshi Wakama
- a Orthopedic Surgery , Osaka Medical College , Osaka , Japan
| | - Nobuhiro Okuno
- a Orthopedic Surgery , Osaka Medical College , Osaka , Japan
| | - Masashi Neo
- a Orthopedic Surgery , Osaka Medical College , Osaka , Japan
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Pontes-Quero GM, García-Fernández L, Aguilar MR, San Román J, Pérez Cano J, Vázquez-Lasa B. Active viscosupplements for osteoarthritis treatment. Semin Arthritis Rheum 2019; 49:171-183. [PMID: 30878154 DOI: 10.1016/j.semarthrit.2019.02.008] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2018] [Revised: 02/05/2019] [Accepted: 02/12/2019] [Indexed: 12/12/2022]
Abstract
OBJECTIVE Osteoarthritis is a chronic, painful and disabling disease which prevalence is increasing in developing countries. Patients with osteoarthritis present a reduced synovial fluid viscoelasticity due to a reduction in concentration and molecular weight of hyaluronic acid. Currently, the main treatment used to restore the compromised rheological properties of synovial fluid is the viscosupplementation by hyaluronic acid injections that can be combined with oral anti-inflammatory drugs for pain relief. Combination of viscosupplements with chemical agents or drugs is emerging as a new strategy to provide a double action of synovial fluid viscoelasticity recovery and the therapeutic effect of the bioactive principle. METHODS In this review, we present the latest research on the combination of viscosupplements with active molecules. We conducted a literature review of articles published in different web search engines and categorized according to the active molecule introduced into the viscosupplement. RESULTS Generally, the introduction of anti-inflammatory molecules have shown to improve pain relief although some cytotoxicity has been demonstrated especially for non-steroidal anti-inflammatory drugs. Other molecules such as antioxidant or disease modifying osteoarthritis drugs have been reported to improve viscosupplementation action. Drug delivery systems combined with hyaluronic acid could enhance the activity of the encapsulated molecules and provide better control over the drug release. Finally, biological approaches such as the use of stem cells or platelet-rich plasma seem to be the most promising strategies for cartilage recovery. CONCLUSIONS Combination therapy of viscosupplements with therapeutic agents, drug delivery systems or regenerative therapies can improve viscosupplementation outcome in terms of pain relief and joint functionality. However, further research is needed in order to reach more conclusive results.
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Affiliation(s)
- Gloria María Pontes-Quero
- Group of Biomaterials, Department of Polymeric Nanomaterials and Biomaterials, Institute of Polymer Science and Technology (ICTP-CSIC), Madrid, Spain; Alodia Farmacéutica SL, Madrid, Spain
| | - Luis García-Fernández
- Group of Biomaterials, Department of Polymeric Nanomaterials and Biomaterials, Institute of Polymer Science and Technology (ICTP-CSIC), Madrid, Spain; Networking Biomedical Research Centre in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Madrid, Spain
| | - María Rosa Aguilar
- Group of Biomaterials, Department of Polymeric Nanomaterials and Biomaterials, Institute of Polymer Science and Technology (ICTP-CSIC), Madrid, Spain; Networking Biomedical Research Centre in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Madrid, Spain.
| | - Julio San Román
- Group of Biomaterials, Department of Polymeric Nanomaterials and Biomaterials, Institute of Polymer Science and Technology (ICTP-CSIC), Madrid, Spain; Networking Biomedical Research Centre in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Madrid, Spain
| | | | - Blanca Vázquez-Lasa
- Group of Biomaterials, Department of Polymeric Nanomaterials and Biomaterials, Institute of Polymer Science and Technology (ICTP-CSIC), Madrid, Spain; Networking Biomedical Research Centre in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Madrid, Spain
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Chiou CS, Wu CM, Dubey NK, Lo WC, Tsai FC, Tung TDX, Hung WC, Hsu WC, Chen WH, Deng WP. Mechanistic insight into hyaluronic acid and platelet-rich plasma-mediated anti-inflammatory and anti-apoptotic activities in osteoarthritic mice. Aging (Albany NY) 2018; 10:4152-4165. [PMID: 30582743 PMCID: PMC6326674 DOI: 10.18632/aging.101713] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2018] [Accepted: 12/06/2018] [Indexed: 12/17/2022]
Abstract
Osteoarthritis (OA) poses a major clinical challenges owing to limited regenerative ability of diseased or traumatized chondrocytes in articular cartilage. Previous studies have determined the individual therapeutic efficacies of hyaluronic acid (HA) and platelet-rich plasma (PRP) on OA; however, the underlying mechanism is still lacking. Therefore, we investigated mechanistic approach of HA+PRP therapy on chondrocyte apoptosis in IL-1β+TNF-α (I+T) treated in vitro OA model, in addition to in vivo anterior cruciate ligament transection-OA mice model. MTT assay showed an enhanced chondrocyte proliferation and viability in HA+PRP-treated group, compared to I+T, I+T/HA, I+T/PRP, I+T/HA+PRP groups. Further, HA+PRP also significantly suppressed ROS, apoptotic cleaved caspase-3 and PARP, p53 and p21 and MMP-1; whereas, cell cycle modulatory proteins including p-ERK, cyclin B1, D1, and E2 were upregulated. The sub-G1 population and TUNEL assay confirmed the higher abundance of healthy chondrocytes in HA+PRP group. A significantly decreased ARS staining in HA+PRP group was also noted, indicating reduced cartilaginous matrix mineralization compared to other groups. Conclusively, compared to HA or PRP, the combined HA+PRP might be a promising therapy for articular cartilage regeneration in osteoarthritic pathology, possibly via augmented anti-inflammatory, anti-oxidative chondrocyte proliferation and inhibited MMP-1 activity and matrix calcification.
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Affiliation(s)
- Chi-Sheng Chiou
- School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei, Taiwan
- Division of Allergy, Immunology and Rheumatology, Department of Internal Medicine, Taipei Medical University Hospital, Taipei, Taiwan
| | - Chi-Ming Wu
- Graduate Institute of Biomedical Materials and Tissue Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei, Taiwan
| | - Navneet Kumar Dubey
- Ceramics and Biomaterials Research Group, Advanced Institute of Materials Science, Ton Duc Thang University, Ho Chi Minh City, Vietnam
- Faculty of Applied Sciences, Ton Duc Thang University, Ho Chi Minh City, Vietnam
| | - Wen-Cheng Lo
- School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
- Department of Neurosurgery, Taipei Medical University Hospital, Taipei, Taiwan
| | - Feng-Chou Tsai
- School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei, Taiwan
| | - Tran Dang Xuan Tung
- School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei, Taiwan
- Stem Cells Center, Van Hanh General Hospital, Ho Chi Minh City, Vietnam
| | - Wei-Ching Hung
- Stem Cell Research Center, College of Oral Medicine, Taipei Medical University, Taiwan
| | - Wei-Che Hsu
- Stem Cell Research Center, College of Oral Medicine, Taipei Medical University, Taiwan
| | - Wei-Hong Chen
- Stem Cell Research Center, College of Oral Medicine, Taipei Medical University, Taiwan
| | - Win-Ping Deng
- School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei, Taiwan
- Stem Cell Research Center, College of Oral Medicine, Taipei Medical University, Taiwan
- Graduate Institute of Basic Medicine, Fu Jen Catholic University, Taipei, Taiwan
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Genemaras AA, Ennis H, Bradshaw B, Kaplan L, Huang CYC. Effects of Anti-Inflammatory Agents on Expression of Early Responsive Inflammatory and Catabolic Genes in Ex Vivo Porcine Model of Acute Knee Cartilage Injury. Cartilage 2018; 9:293-303. [PMID: 29986604 PMCID: PMC6042029 DOI: 10.1177/1947603516684589] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
Objective Early intervention therapies targeting inflammation and cell death during the acute phase of cartilage injury have the potential to prevent posttraumatic osteoarthritis. The objective of this study was to investigate the effects of interleukin receptor antagonist protein (IRAP), hyaluronan (HA), dexamethasone (DEX), and mesenchymal stem cell (MSC) treatment on the expression of established genetic markers for matrix degradation, apoptosis, and inflammation in articular cartilage during the acute phase of injury. Design A custom impact device was used to create replicable injury ex vivo to intact porcine knee joint. One hour after impact, IRAP, HA, DEX, or MSCs was intra-articularly injected. At 8 hours postinjury, cartilage and meniscus samples were harvested for genetic expression analysis. Expression of miR-27b, miR-140, miR-125b, miR-16, miR-34a, miR-146a, miR-22, ADAMTS-4, ADAMTS-5, MMP-3, IL-1β, and TNF-α was analyzed by real-time polymerase chain reaction. Results At 8 hours postinjury, expression of ADAMTS-4, ADAMTS-5, MMP-3, IL-1β, and TNF-α in cartilage was significantly decreased in IRAP- and DEX-treated joints as compared to nontreated injured joints, whereas only IRAP upregulated expression of miR-140, miR-125b, miR-27b, miR-146a, and miR-22 in cartilage. HA and MSC treatments had no significant effects on catabolic and inflammatory gene expression in cartilage. However, HA treatment significantly upregulated expression of all miRNAs except miR-16. In addition, the treatments tested also exhibited significant influences on meniscus. Conclusions This study provides a valuable starting point for further research into potential targets for and efficacy of various early intervention strategies that may delay or prevent the progression of posttraumatic osteoarthritis after acute cartilage injury.
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MESH Headings
- ADAMTS4 Protein/drug effects
- ADAMTS4 Protein/genetics
- ADAMTS5 Protein/drug effects
- ADAMTS5 Protein/genetics
- Animals
- Anti-Inflammatory Agents/metabolism
- Cartilage, Articular/drug effects
- Cartilage, Articular/injuries
- Cartilage, Articular/metabolism
- Cell Death/drug effects
- Cells, Cultured/metabolism
- Chondrocytes/drug effects
- Chondrocytes/metabolism
- Dexamethasone/administration & dosage
- Dexamethasone/therapeutic use
- Gene Expression
- Hyaluronic Acid/administration & dosage
- Hyaluronic Acid/therapeutic use
- Inflammation/metabolism
- Injections, Intra-Articular/methods
- Matrix Metalloproteinase 3/drug effects
- Matrix Metalloproteinase 3/genetics
- Meniscus/drug effects
- Meniscus/metabolism
- Mesenchymal Stem Cell Transplantation/methods
- MicroRNAs/genetics
- Models, Animal
- Osteoarthritis, Knee/genetics
- Osteoarthritis, Knee/prevention & control
- Receptors, Interleukin/antagonists & inhibitors
- Receptors, Interleukin/therapeutic use
- Swine
- Tumor Necrosis Factor-alpha/drug effects
- Tumor Necrosis Factor-alpha/genetics
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Affiliation(s)
- Amaris A. Genemaras
- Department of Biomedical Engineering,
College of Engineering, University of Miami, Coral Gables, FL, USA
| | - Hayley Ennis
- Department of Biomedical Engineering,
College of Engineering, University of Miami, Coral Gables, FL, USA
| | - Brad Bradshaw
- Department of Biomedical Engineering,
College of Engineering, University of Miami, Coral Gables, FL, USA
| | - Lee Kaplan
- Department of Biomedical Engineering,
College of Engineering, University of Miami, Coral Gables, FL, USA
- Department of Orthopedics, Division of
Sports Medicine, University of Miami Miller School of Medicine, Miami, FL, USA
| | - C.-Y. Charles Huang
- Department of Biomedical Engineering,
College of Engineering, University of Miami, Coral Gables, FL, USA
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Smyth NA, Ross KA, Haleem AM, Hannon CP, Murawski CD, Do HT, Kennedy JG. Platelet-Rich Plasma and Hyaluronic Acid Are Not Synergistic When Used as Biological Adjuncts with Autologous Osteochondral Transplantation. Cartilage 2018; 9:321-328. [PMID: 29156980 PMCID: PMC6042028 DOI: 10.1177/1947603517690022] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
UNLABELLED Introduction Autologous osteochondral transplantation (AOT) is a treatment for osteochondral lesions with known concerns, including histological degradation of the graft and poor cartilage integration. Platelet-rich plasma (PRP) and hyaluronic acid (HA) have been described has having the potential to improve results. The aim of this study was to evaluate the effect of PRP and HA on AOT in a rabbit model. Methods Thirty-six rabbits underwent bilateral knee AOT treated with either the biological adjunct (PRP, n = 12; HA, n = 12; PRP + HA, n = 12) or saline (control). PRP and HA were administered as an intra-articular injection. The rabbits were euthanized at 3, 6, or 12 weeks postoperatively. The graft sections were assessed using the modified International Cartilage Repair Society (ICRS) scoring system. The results from the PRP alone group is from previously published data. Results The mean modified ICRS histological score for the PRP-treated group was higher than its control ( P = 0.002). The mean modified ICRS histological score for the HA-treated group showed no difference compared with its control ( P = 0.142). The mean modified ICRS histological score for the PRP + HA-treated group was higher than its control ( P = 0.006). There was no difference between the mean modified ICRS scores of the PRP- and the PRP + HA-treated grafts ( P = 0.445). Conclusion PRP may decrease graft degradation and improve chondral integration in an animal model. In this model, the addition of HA was not synergistic for the parameters assessed. LEVEL OF EVIDENCE Basic science, Level V. CLINICAL RELEVANCE PRP can be used as an adjunct to AOT, which may decrease graft degeneration and improve clinical outcomes. HA may not influence AOT.
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Affiliation(s)
- Niall A. Smyth
- University of Miami Miller School of Medicine, Miami, FL, USA
| | - Keir A. Ross
- University of Maryland School of Medicine, New York, NY, USA
| | - Amgad M. Haleem
- University of Oklahoma School of Medicine, New York, NY, USA
| | | | | | - Huong T. Do
- Hospital for Special Surgery, New York, NY, USA
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Huang Y, Cai GQ, Peng JP, Shen C. Glucocorticoids induce apoptosis and matrix metalloproteinase-13 expression in chondrocytes through the NOX4/ROS/p38 MAPK pathway. J Steroid Biochem Mol Biol 2018. [PMID: 29526705 DOI: 10.1016/j.jsbmb.2018.03.001] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Based on the results from our previous study, dexamethasone (Dex) increases reactive oxygen species (ROS) levels and subsequently induces cell death and matrix catabolism in chondrocytes. Nevertheless, the mechanism underlying this phenomenon remains unclear. Nicotinamide adenine dinucleotide (phosphate) (NADPH) oxidase 4 (NOX4) is one of the major enzymes responsible for intracellular ROS production during the inflammatory process. The objective of the current study was to investigate the role of NOX4 in Dex-induced ROS over-production. Healthy chondrocytes were harvested from the cartilage debris from 6 female patients. NOX4 and p38 mitogen-activated protein kinase (MAPK) expression levels in these cells were evaluated in the presence of Dex. Changes in the number of apoptotic and viable Dex-treated chondrocytes were recorded after the cells were treated with NOX and p38 MAPK inhibitors. Changes in matrix metalloproteinase 13 (MMP-13) expression levels in Dex-treated chondrocytes were also investigated. The Dex treatment increased NOX4 expression via the glucocorticoid receptor (GR). Treatment of cells with apocynin, a NOX inhibitor, decreased intracellular ROS levels and inhibited p38 MAPK activation. Treatment of cells with a ROS scavenger also reduced p38 MAPK expression. Treatment of cells with a NOX inhibitor, ROS scavenger and p38 MAPK inhibitor rescued chondrocytes from Dex-induced apoptosis. Moreover, treatment of cells with these agents blocked MMP-13 expression in Dex-treated chondrocytes. NOX4 silencing also suppressed p38 MAPK and MMP-13 expression. Dex triggered apoptosis and MMP-13 expression through the NOX4/ROS/p38 MAPK signaling pathway. NOX4 may be a therapeutic target in the management of Dex-induced complications.
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Affiliation(s)
- Ying Huang
- Department of Anesthesiology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, 200092, Shanghai, China
| | - Gui-Quan Cai
- Department of Orthopedics, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, 200092, Shanghai, China
| | - Jian-Ping Peng
- Department of Orthopedics, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, 200092, Shanghai, China
| | - Chao Shen
- Department of Orthopedics, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, 200092, Shanghai, China.
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Hemmati-Sadeghi S, Ringe J, Dehne T, Haag R, Sittinger M. Hyaluronic Acid Influence on Normal and Osteoarthritic Tissue-Engineered Cartilage. Int J Mol Sci 2018; 19:ijms19051519. [PMID: 29783732 PMCID: PMC5983669 DOI: 10.3390/ijms19051519] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2018] [Revised: 05/08/2018] [Accepted: 05/15/2018] [Indexed: 12/27/2022] Open
Abstract
The aim of this study is to identify gene expression profiles associated with hyaluronic acid (HA) treatment of normal and osteoarthritis (OA)-like tissue-engineered cartilage. 3D cartilage micromasses were treated with tumour necrosis factor-α (TNF-α) (OA-inducer) and/or HA for 7 days. Viability was examined by PI/FDA staining. To document extracellular matrix (ECM) formation, glycosaminoglycans (GAG) were stained with Safranin-O and cartilage-specific type II collagen was detected immunohistochemically. Genome-wide gene expression was determined using microarray analysis. Normal and OA-like micromasses remained vital and showed a spherical morphology and homogenous cell distribution regardless of the treatment. There was no distinct difference in immunolabeling for type II collagen. Safranin-O staining demonstrated a typical depletion of GAG in TNF-α-treated micromasses (−73%), although the extent was limited in the presence of HA (−39%). The microarray data showed that HA can influence the cartilage metabolism via upregulation of TIMP3 in OA-like condition. The upregulation of VEGFA and ANKRD37 genes implies a supportive role of HA in cartilage maturation and survival. The results of this study validate the feasibility of the in vitro OA model for the investigation of HA. On the cellular level, no inhibiting or activating effect of HA was shown. Microarray data demonstrated a minor impact of HA on gene expression level.
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Affiliation(s)
- Shabnam Hemmati-Sadeghi
- Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin-Brandenburg School for Regenerative Therapies, 10117 Berlin, Germany.
- Institut für Chemie und Biochemie, Freie Universität Berlin, 14195 Berlin, Germany.
- Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Tissue Engineering Laboratory, Berlin-Brandenburg Center for Regenerative Therapies & Department of Rheumatology and Clinical Immunology, 10117 Berlin, Germany.
| | - Jochen Ringe
- Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Tissue Engineering Laboratory, Berlin-Brandenburg Center for Regenerative Therapies & Department of Rheumatology and Clinical Immunology, 10117 Berlin, Germany.
| | - Tilo Dehne
- Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Tissue Engineering Laboratory, Berlin-Brandenburg Center for Regenerative Therapies & Department of Rheumatology and Clinical Immunology, 10117 Berlin, Germany.
| | - Rainer Haag
- Institut für Chemie und Biochemie, Freie Universität Berlin, 14195 Berlin, Germany.
| | - Michael Sittinger
- Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Tissue Engineering Laboratory, Berlin-Brandenburg Center for Regenerative Therapies & Department of Rheumatology and Clinical Immunology, 10117 Berlin, Germany.
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Heck BE, Park JJ, Makani V, Kim EC, Kim DH. PPAR-δ Agonist With Mesenchymal Stem Cells Induces Type II Collagen-Producing Chondrocytes in Human Arthritic Synovial Fluid. Cell Transplant 2018; 26:1405-1417. [PMID: 28901183 PMCID: PMC5680970 DOI: 10.1177/0963689717720278] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
Osteoarthritis (OA) is an inflammatory joint disease characterized by degeneration of articular cartilage within synovial joints. An estimated 27 million Americans suffer from OA, and the population is expected to reach 67 million in the United States by 2030. Thus, it is urgent to find an effective treatment for OA. Traditional OA treatments have no disease-modifying effect, while regenerative OA therapies such as autologous chondrocyte implantation show some promise. Nonetheless, current regenerative therapies do not overcome synovial inflammation that suppresses the differentiation of mesenchymal stem cells (MSCs) to chondrocytes and the expression of type II collagen, the major constituent of functional cartilage. We discovered a synergistic combination that overcame synovial inflammation to form type II collagen-producing chondrocytes. The combination consists of peroxisome proliferator–activated receptor (PPAR) δ agonist, human bone marrow (hBM)-derived MSCs, and hyaluronic acid (HA) gel. Interestingly, those individual components showed their own strong enhancing effects on chondrogenesis. GW0742, a PPAR-δ agonist, greatly enhanced MSC chondrogenesis and the expression of type II collagen and glycosaminoglycan (GAG) in hBM-MSC-derived chondrocytes. GW0742 also increased the expression of transforming growth factor β that enhances chondrogenesis and suppresses cartilage fibrillation, ossification, and inflammation. HA gel also increased MSC chondrogenesis and GAG production. However, neither GW0742 nor HA gel could enhance the formation of type II collagen-producing chondrocytes from hBM-MSCs within human OA synovial fluid. Our data demonstrated that the combination of hBM-MSCs, PPAR-δ agonist, and HA gel significantly enhanced the formation of type II collagen-producing chondrocytes within OA synovial fluid from 3 different donors. In other words, the novel combination of PPAR-δ agonist, hBM-MSCs, and HA gel can overcome synovial inflammation to form type II collagen cartilage within human OA synovial fluid. This novel articularly injectable formula could improve OA treatment in the future clinical application.
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Affiliation(s)
- Bruce E Heck
- 1 NWO Stem Cure, LLC, Findlay, OH, USA.,2 Northwest Ohio Orthopedics and Sports Medicine, Findlay, OH, USA
| | - Joshua J Park
- 3 Department of Neurosciences, University of Toledo College of Medicine and Life Science, Toledo, OH, USA
| | - Vishruti Makani
- 3 Department of Neurosciences, University of Toledo College of Medicine and Life Science, Toledo, OH, USA
| | - Eun-Cheol Kim
- 4 Department of Oral and Maxillofacial Pathology, School of Dentistry, Kyung Hee University, Seoul, Republic of Korea
| | - Dong Hyun Kim
- 1 NWO Stem Cure, LLC, Findlay, OH, USA.,2 Northwest Ohio Orthopedics and Sports Medicine, Findlay, OH, USA.,5 Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
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The pericellular hyaluronan of articular chondrocytes. Matrix Biol 2018; 78-79:32-46. [PMID: 29425696 DOI: 10.1016/j.matbio.2018.02.005] [Citation(s) in RCA: 63] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2017] [Revised: 02/02/2018] [Accepted: 02/03/2018] [Indexed: 02/01/2023]
Abstract
The story of hyaluronan in articular cartilage, pericellular hyaluronan in particular, essentially is also the story of aggrecan. Without properly tethered aggrecan, the load bearing function of cartilage is compromised. The anchorage of aggrecan to the cell surface only occurs due to the binding of aggrecan to hyaluronan-with hyaluronan tethered either to a hyaluronan synthase or by multivalent binding to CD44. In this review, details of hyaluronan synthesis are discussed including how HAS2 production of hyaluronan is necessary for normal chondrocyte development and matrix assembly, how an abundance or deficit of pericellular hyaluronan alters chondrocyte metabolism, and whether hyaluronan size matters or changes with aging or disease. The biomechanical role and matrix assembly function of hyaluronan in addition to the functions of hyaluronidases are discussed. The turnover of hyaluronan is considered including mechanisms by which its turnover, at least in part, is mediated by endocytosis by chondrocytes and regulated by aggrecan degradation. Differences between turnover and clearance of newly synthesized hyaluronan and aggrecan versus the half-life of hyaluronan remaining within the inter-territorial matrix of cartilage are discussed. The release of neutral pH-acting hyaluronidase activity remains one unanswered question concerning the loss of cartilage hyaluronan in osteoarthritis. Signaling events driven by changes in hyaluronan-chondrocyte interactions may involve a chaperone function of CD44 with other receptors/cofactors as well as the changes in hyaluronan production functioning as a metabolic rheostat.
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Avenoso A, D'Ascola A, Scuruchi M, Mandraffino G, Calatroni A, Saitta A, Campo S, Campo GM. Hyaluronan in the experimental injury of the cartilage: biochemical action and protective effects. Inflamm Res 2018; 67:5-20. [PMID: 28803264 DOI: 10.1007/s00011-017-1084-9] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2017] [Revised: 07/25/2017] [Accepted: 07/29/2017] [Indexed: 02/07/2023] Open
Abstract
INTRODUCTION Our knowledge of extracellular matrix (ECM) structure and function has increased enormously over the last decade or so. There is evidence demonstrating that ECM provides signals affecting cell adhesion, shape, migration, proliferation, survival, and differentiation. ECM presents many domains that become active after proteolytic cleavage. These active ECM fragments are called matrikines which play different roles; in particular, they may act as potent inflammatory mediators during cartilage injury. FINDINGS A major component of the ECM that undergoes dynamic regulation during cartilage damage and inflammation is the non-sulphated glycosaminoglycan (GAG) hyaluronan (HA). In this contest, HA is the most studied because of its different activity due to the different polymerization state. In vivo evidences have shown that low molecular weight HA exerts pro-inflammatory action, while high molecular weight HA possesses anti-inflammatory properties. Therefore, the beneficial HA effects on arthritis are not only limited to its viscosity and lubricant action on the joints, but it is especially due to a specific and effective anti-inflammatory activity. Several in vitro experimental investigations demonstrated that HA treatment may regulate different biochemical pathways involved during the cartilage damage. Emerging reports are suggesting that the ability to recognize receptors both for the HA degraded fragments, whether for the high-polymerized native HA involve interaction with integrins, toll-like receptors (TLRs), and the cluster determinant (CD44). The activation of these receptors induced by small HA fragments, via the nuclear factor kappa-light-chain enhancer of activated B cell (NF-kB) mediation, directly or other different pathways, produces the transcription of a large number of damaging intermediates that lead to cartilage erosion. CONCLUSIONS This review briefly summarizes a number of findings of the recent studies focused on the protective effects of HA, at the different polymerization states, on experimental arthritis in vitro both in animal and human cultured chondrocytes.
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Affiliation(s)
- Angela Avenoso
- Department of Biomedical and Dental Sciences and Morphofunctional Images, Policlinico Universitario, University of Messina, 98125, Messina, Italy
| | - Angela D'Ascola
- Department of Clinical and Experimental Medicine, University of Messina, Policlinico Universitario, Torre Biologica, 5° piano, Via C. Valeria, 98125, Messina, Italy
| | - Michele Scuruchi
- Department of Clinical and Experimental Medicine, University of Messina, Policlinico Universitario, Torre Biologica, 5° piano, Via C. Valeria, 98125, Messina, Italy
| | - Giuseppe Mandraffino
- Department of Clinical and Experimental Medicine, University of Messina, Policlinico Universitario, Torre Biologica, 5° piano, Via C. Valeria, 98125, Messina, Italy
| | - Alberto Calatroni
- Department of Clinical and Experimental Medicine, University of Messina, Policlinico Universitario, Torre Biologica, 5° piano, Via C. Valeria, 98125, Messina, Italy
| | - Antonino Saitta
- Department of Clinical and Experimental Medicine, University of Messina, Policlinico Universitario, Torre Biologica, 5° piano, Via C. Valeria, 98125, Messina, Italy
| | - Salvatore Campo
- Department of Biomedical and Dental Sciences and Morphofunctional Images, Policlinico Universitario, University of Messina, 98125, Messina, Italy
| | - Giuseppe M Campo
- Department of Clinical and Experimental Medicine, University of Messina, Policlinico Universitario, Torre Biologica, 5° piano, Via C. Valeria, 98125, Messina, Italy.
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Abstract
Objective Summarize the biologic effects of Supartz FX for knee osteoarthritis (OA), the first worldwide clinically approved intra-articular (IA) hyaluronic acid (HA) product. Design To determine the mechanism of action from preclinical and clinical studies, a literature search was conducted of Supartz FX using academic databases from 1987 to 2016. Articles on Supartz FX that deal with its mechanisms of action were extracted, categorized, and reviewed. Results Supartz FX has 2 potential mechanisms of action: (1) biomechanical: IA Supartz FX directly improves the viscoelasticity and lubrication of synovial fluid; (2) physiologic: IA Supartz FX penetrates synovium and cartilage tissues to reach HA receptors on the surface of synoviocytes and chondrocytes. In synovium, suppression of gene expression in inflammatory mediators results in improved endogenous HA production, improved properties of synovial fluid, and reduction in pain. In cartilage, suppression of gene expression of collagenases and aggrecanases suppresses cartilage degeneration. Conclusion The net results of basic and clinical studies is that IA Supartz FX provides a more favorable biomechanical and functional environment in the knee joint. Hence, it is not only a lubricant but is also physiologically active. These actions may help explain both short- and long-term improvement in pain and function often achieved from IA Supartz FX in knee OA.
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Affiliation(s)
- Roy D. Altman
- Department of Medicine, Division of Rheumatology and Immunology, David Geffen School of Medicine, University of California Los Angeles, CA, USA,Roy D. Altman, Division of Rheumatology and Immunology, David Geffen School of Medicine, University of California at Los Angeles, 1000 Veterans Ave, Los Angeles 90024, CA, USA.
| | - Vinod Dasa
- Department of Orthopaedics, Louisiana State University Health Sciences Center, New Orleans, LA, USA
| | - Jun Takeuchi
- Pharmaceuticals Information Group, Seikagaku Corporation, Tokyo, Japan
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Ozdamar SM, Alev B, Yarat A. The impact of arthrocentesis with and without hyaluronic acid injection in the prognosis and synovial fluid myeloperoxidase levels of patients with painful symptomatic internal derangement of temporomandibular joint: a randomised controlled clinical trial. J Oral Rehabil 2017; 44:73-80. [PMID: 27973684 DOI: 10.1111/joor.12467] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/04/2016] [Indexed: 11/28/2022]
Abstract
We aimed to assess the relationship between myeloperoxidase (MPO) and internal derangement (ID) of temporomandibular joint (TMJ) and effects of arthrocentesis procedure, either alone or in combination with hyaluronic acid (HA) injection on the prognosis of ID of TMJ. A prospective randomised controlled trial has been conducted through patients, who underwent arthrocentesis for the treatment of ID of TMJ, were randomly divided into two groups. Group SS (n = 10) and Group HA (n = 14) patients were assigned 0·9% NaCl solution and sodium hyaluronate intra-articularly, respectively. Synovial fluid samples were assayed for MPO at the time of arthrocentesis and pain visual analogue scale (VAS) and maximum mouth opening (MMO) scores were recorded at pre- and post-operative periods as well as first-week, first-month and third-month intervals. There was a statistically significant decrease in MPO levels between the first to second arthrocenteses only in Group 2 (P = 0·001). Both VAS scores and MMO measurements decreased in the course of time following arthrocentesis and do not differ between the patients administered HA or SS. Similarly MPO levels do not change significantly between the two groups at either first or second arthrocenteses. In HA group, MPO levels significantly decreased from first to second sessions. In HA group, MPO levels decreased significantly only in patients with clinical success. Arthrocentesis procedure improves both pain VAS and MMO scores in the course of time, but these parameters do not differ between patients receiving either HA or SS. HA significantly reduces levels of MPO in synovial fluid, but SS does not. HA appears to alleviate inflammation inside the TMJ in patients with TMJ-ID.
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Affiliation(s)
- S M Ozdamar
- Department of Oral and Dental Surgery, Faculty of Dentistry, Marmara University, Basibuyuk, Maltepe, Istanbul, Turkey
| | - B Alev
- Basic Medical Sciences, Biochemistry, Faculty of Dentistry, Marmara University, Basibuyuk, Maltepe, Istanbul, Turkey
| | - A Yarat
- Basic Medical Sciences, Biochemistry, Faculty of Dentistry, Marmara University, Basibuyuk, Maltepe, Istanbul, Turkey
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Muramatsu K, Tajima Y, Kaneko R, Yanagita Y, Hirai H, Hiura N. Characterization of poly(L-glutamic acid)-grafted hyaluronan as a novel candidate medicine and biomedical device for intra-articular injection. J Biomed Mater Res A 2017; 105:3006-3016. [PMID: 28675666 DOI: 10.1002/jbm.a.36155] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2016] [Revised: 05/30/2017] [Accepted: 06/15/2017] [Indexed: 12/31/2022]
Affiliation(s)
- Kazuaki Muramatsu
- Division of Life Science and Engineering; School of Science and Engineering, Tokyo Denki University, Ishizaka, Hatoyama-cho, Hiki-gun; Saitama 350-0394 Japan
| | - Yuya Tajima
- Division of Life Science and Engineering; School of Science and Engineering, Tokyo Denki University, Ishizaka, Hatoyama-cho, Hiki-gun; Saitama 350-0394 Japan
| | - Rin Kaneko
- Division of Life Science and Engineering; School of Science and Engineering, Tokyo Denki University, Ishizaka, Hatoyama-cho, Hiki-gun; Saitama 350-0394 Japan
| | - Yuta Yanagita
- Division of Life Science and Engineering; School of Science and Engineering, Tokyo Denki University, Ishizaka, Hatoyama-cho, Hiki-gun; Saitama 350-0394 Japan
| | - Hiroyuki Hirai
- Division of Life Science and Engineering; School of Science and Engineering, Tokyo Denki University, Ishizaka, Hatoyama-cho, Hiki-gun; Saitama 350-0394 Japan
| | - Nana Hiura
- Division of Life Science and Engineering; School of Science and Engineering, Tokyo Denki University, Ishizaka, Hatoyama-cho, Hiki-gun; Saitama 350-0394 Japan
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Kubomura D, Ueno T, Yamada M, Nagaoka I. Evaluation of the chondroprotective action of N-acetylglucosamine in a rat experimental osteoarthritis model. Exp Ther Med 2017; 14:3137-3144. [PMID: 28912864 DOI: 10.3892/etm.2017.4849] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2016] [Accepted: 04/28/2017] [Indexed: 01/22/2023] Open
Abstract
It has been demonstrated that oral administration of N-acetylglucosamine (GlcNAc) alleviates the symptoms of osteoarthritis (OA). The aim of the present study was to elucidate the molecular mechanisms for the chondroprotective action of GlcNAc in OA. Biomarkers for type II collagen degradation and synthesis were evaluated, as were histopathological changes, using a rat anterior cruciate ligament transection (ACLT)-induced OA model. Changes in the expression of genes in the cartilage were assessed via DNA microarray and reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The results indicated that ACLT induced histopathological changes of articular cartilage, whereas oral administration of GlcNAc (1,000 mg/kg/day for 28 days) significantly suppressed these changes. Additionally, GlcNAc significantly decreased levels of a type II collagen degradation marker in sera compared with that in the ACLT group, although there were no significant changes in the levels of a type II collagen synthesis marker. Furthermore, DNA microarray and reverse transcription-quantitative polymerase chain reaction results demonstrated that GlcNAc treatment downregulated the expression of periostin, which is likely involved in the degradation of cartilage, whereas GlcNAc upregulated the expression of lipocalin 2, which is involved in the regulation of chondrocyte proliferation and differentiation. In conclusion, the results of the present study suggest that GlcNAc is able to suppress the histopathological changes induced by OA and exhibits a chondroprotective action by inhibiting type II collagen degradation in the articular cartilage, possibly via modulation of the expression of inflammatory and chondroprotective molecules, including periostin and lipocalin 2.
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Affiliation(s)
- Daiki Kubomura
- Yaizu Suisankagaku Industry Co., Ltd., Yaizu, Shizuoka 425-8570, Japan
| | - Tomoya Ueno
- Yaizu Suisankagaku Industry Co., Ltd., Yaizu, Shizuoka 425-8570, Japan
| | - Masanori Yamada
- Yaizu Suisankagaku Industry Co., Ltd., Yaizu, Shizuoka 425-8570, Japan
| | - Isao Nagaoka
- Department of Host Defense and Biochemical Research, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan
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Gumustas SA, Oznam K, Mutlu CA, Kaya YE, Yilmaz I, Isyar M, Guzelant AY, Guler O, Akkaya S, Mahirogullari M. Are We Using Slow-Acting Symptomatic Chondroprotective Drugs Conscious Enough? Open Orthop J 2017; 11:533-540. [PMID: 28694893 PMCID: PMC5470068 DOI: 10.2174/1874325001711010533] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2017] [Revised: 04/20/2017] [Accepted: 05/14/2017] [Indexed: 12/26/2022] Open
Abstract
Background: Osteochondral injuries constitute an entity that is widespread and can be seen in patients of all ages. Actual treatment modalities aim to relieve pain, obtain full range of movement of the joint, and improve the quality of life. There are many slow-acting chondroprotective agents prevalently used in the United States that are classified as nutritional support but not as medicines . This study presents the importance of clinical adverse effect profiles as well as the pharmacological mechanism of action and application of combinations of drugs that are widely prescribed and not subjected to control. Methods: Electronic databases were searched with keywords about the chondroprotective drugs without any language restriction. Evaluations of the descriptive statistics were represented via Microsoft Office Excel 2010 lists in the form of a mean±standard deviation or frequency (%). The first evaluation showed that 1502 studies were potentially relevant. Following exclusion of the 1277 studies which were not clinical, full versions of the remaining 225 studies were subjected to further evaluation. No controlled, blinded, randomized and/or comparative studies met the inclusion criteria of the study, and no studies evaluated the comparative clinical results of the hyaluronan of different molecular weights. Results: The findings of this study concluded that especially when prescribing drugs with ingredients like GS and CS, many patients’ pre-existing conditions must be considered, such as whether the patient has a glucose intolerance or not. Additionally, mineral toxication should be considered since the drugs contain minerals, and after the application of injected hyaluronan, complications should be considered. Conclusion: Clinical, controlled and comparative studies about the use of chondroprotective drugs must be performed to define the benefits of these drugs, if any, in order to determine the most suitable time for operative intervention.
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Affiliation(s)
- Seyit Ali Gumustas
- Department of Orthopaedic and Traumatology, Dr.Lutfi Kirdar Kartal Training and Research Hospital, 34865, Istanbul,Turkey
| | - Kadir Oznam
- Department of Orthopaedic and Traumatology, Istanbul Medipol University School of Medicine, 34214Istanbul, Turkey
| | - Cagri Ata Mutlu
- Department of Medical Sciences, Acibadem Universitiy School of Medicine, 34752Istanbul, Turkey
| | - Yasin Emre Kaya
- Department of Orthopaedic and Traumatology, Republic of Turkey, Ministry of Health, State Hospital, Corlu, 59850Tekirdag, Turkey
| | - Ibrahim Yilmaz
- Department of Medical Pharmacology, Istanbul Medipol University School of Medicine, 34810Istanbul, Turkey
| | - Mehmet Isyar
- Department of Orthopaedic and Traumatology, Acibadem Hospitals Group, Kadikoy, 34718Istanbul, Turkey
| | - Aliye Yıldırım Guzelant
- Department of Physical Medicine and Rehabilitation, Namik Kemal University School of Medicine, 59030Tekirdag, Turkey
| | - Olcay Guler
- Department of Orthopaedic and Traumatology, Istanbul Medipol University School of Medicine, 34214Istanbul, Turkey
| | - Semih Akkaya
- Department of Orthopaedic and Traumatology, Private Denizli Surgery Hospital, 20070Denizli, Turkey
| | - Mahir Mahirogullari
- Department of Orthopaedic and Traumatology, Memorial Health Group, 34750Istanbul, Turkey
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Chitosan-Based Thermosensitive Hydrogel for Controlled Drug Delivery to the Temporomandibular Joint. J Craniofac Surg 2017; 27:735-40. [PMID: 27100649 DOI: 10.1097/scs.0000000000002588] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Intra-articular injections of hyaluronic acid (HA) and corticosteroids have been extensively used in treating temporomandibular disorders. However, rapid clearance from the site of injection is a major concern that is commonly managed by frequent dosing, which is not without complications. This study aimed to determine the suitability of thermosensitive chitosan-based hydrogels for intra-articular controlled release of drugs in the rabbit temporomandibular joint (TMJ). A series of hydrogels were prepared using different chitosan (Ch) to β-glycerophosphate (β-GP) ratios. The gelation time, swelling ratio, the shape, and surface morphology of the prepared gels were investigated to select the formulation with optimum characteristics. The left TMJ in 13 adult male New Zealand white rabbits was injected with 0.2 mL of Chitosan/β-glycerophosphate/HA while the right TMJ was injected with 0.2 mL of control solution of HA. Hyaluronic acid concentrations in experimental and control groups were measured using Hyaluronan Quantikine Enzyme-Linked Immunosorbent Assay Kit. In vitro characterization showed that both the Ch:β-GP ratio and incorporation of HA had a significant effect on gelation time, degree of swelling, and surface morphology of the hydrogels. No morphological changes were observed in the joints in both groups. The mean concentration of HA in the experimental joints after 7 days (1339.79 ± 244.98 μg/g) was significantly higher than that in the control (474.52 ± 79.36 μg/g). In conclusion, the chitosan-based thermosensitive hydrogel can be considered as a promising controlled drug release system to the TMJ in a rabbit model that would potentially overcome many of the current limitations of intra-articular formulations.
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Kubomura D, Ueno T, Yamada M, Tomonaga A, Nagaoka I. Effect of N-acetylglucosamine administration on cartilage metabolism and safety in healthy subjects without symptoms of arthritis: A case report. Exp Ther Med 2017; 13:1614-1621. [PMID: 28413518 PMCID: PMC5377572 DOI: 10.3892/etm.2017.4140] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2015] [Accepted: 12/09/2016] [Indexed: 12/27/2022] Open
Abstract
N-acetylglucosamine (GlcNAc) is a widely accepted treatment for osteoarthritis (OA); however, its effect on healthy individuals is poorly understood. To evaluate the effect of GlcNAc administration on healthy subjects that do not exhibit symptoms of arthritis, the present randomized, double-blind, placebo-controlled study was performed. In the present study, 68 male and female Japanese participants, without symptomatic and radiographic evidence of OA, were enrolled and randomly allocated to receive placebo or GlcNAc (500 or 1,000 mg/day) for 16 weeks. Effects were evaluated using biomarkers for type II collagen degradation and synthesis, collagen type II cleavage (C2C), procollagen type II carboxy-terminal propeptide (PIICP) and their ratio (C2C/PIICP). Furthermore, safety assessments were performed via physical parameters, hematology, blood biochemistry and urinalysis. The results indicated that there was no significant change in the biomarkers for type II collagen degeneration and synthesis during and after the intervention with the placebo and two GlcNAc groups. However, subgroup analysis using subjects with impaired cartilage metabolism (who exhibited enhanced type II collagen degradation and reduced type II collagen synthesis) indicated that the C2C levels were significantly decreased at 8 (P<0.05) and 16 (P<0.01) weeks during the intervention in the two GlcNAc (500 mg and 1,000 mg/day) groups, compared with the placebo group. In contrast, PIICP levels were not notably different in the placebo and two GlcNAc groups. The C2C/PIICP ratio was markedly decreased at 12 and 16 weeks during the intervention in the two GlcNAc groups, compared with the placebo group. Moreover, no supplement-related adverse events were observed during and after the intervention. In conclusion, these observations indicate that oral administration of GlcNAc at doses of 500 and 1,000 mg/day improves cartilage metabolism in healthy subjects without apparent adverse effects.
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Affiliation(s)
- Daiki Kubomura
- Yaizu Suisankagaku Industry Co., Ltd., Yaizu, Shizuoka 425-8570, Japan
| | - Tomoya Ueno
- Yaizu Suisankagaku Industry Co., Ltd., Yaizu, Shizuoka 425-8570, Japan
| | - Masanori Yamada
- Yaizu Suisankagaku Industry Co., Ltd., Yaizu, Shizuoka 425-8570, Japan
| | | | - Isao Nagaoka
- Department of Host Defense and Biochemical Research, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan
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Furuta J, Ariyoshi W, Okinaga T, Takeuchi J, Mitsugi S, Tominaga K, Nishihara T. High molecular weight hyaluronic acid regulates MMP13 expression in chondrocytes via DUSP10/MKP5. J Orthop Res 2017; 35:331-339. [PMID: 27101204 DOI: 10.1002/jor.23266] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2015] [Accepted: 04/18/2016] [Indexed: 02/04/2023]
Abstract
To determine the effect of high molecular weight hyaluronic acid (HA) on matrix metalloproteinase 13 (MMP13) expression induced by tumor necrosis factor α (TNF-α) in chondrocytes. Human chondrocytic C28/I2 cells were incubated with TNF-α and HA. In some experiments, the cells were pre-incubated with a CD44 function-blocking monoclonal antibody (CD44 mAb) prior to addition of TNF-α and HA. The expression of MMP13 was determined by real-time reverse-transcription polymerase chain reaction (RT-PCR) and an enzyme linked immunosorbent assay, while the phosphorylation of signaling molecules was measured by western blot analysis. The transcriptional activity of activator protein 1 (AP-1) was analyzed by a reporter assay. To further clarify the molecular mechanisms of HA in MMP13 regulation, the expression level of dual-specificity protein phosphatase 10 (DUSP10)/mitogen-activated protein kinases phosphatase 5 (MKP5) in HA-treated chondrocytes was assessed by real-time RT-PCR, western blotting, and immunofluorescence microscopy. HA decreased MMP13 mRNA and protein expression induced by TNF-α. Blockage of HA-CD44 binding by CD44 mAb suppressed HA-mediated inhibition of MMP13. HA inhibited transient phosphorylation of p38 mitogen-activated protein kinase (MAPK) and c-jun NH2 -terminal kinase (JNK) induced by TNF-α. Reporter assay findings also revealed that pre-treatment with HA inhibited the transcriptional activity of AP-1 mediated by TNF-α. Moreover, HA induced the expression of DUSP10/MKP5, a negative regulator of p38 MAPK and JNK pathways. These results indicate that HA-CD44 interactions downregulate TNF-α-induced MMP13 expression via regulation of DUSP10/MKP5, suggesting that HA plays an important role as a regulatory factor in cartilage degradation. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:331-339, 2017.
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Affiliation(s)
- Junya Furuta
- Division of Infections and Molecular Biology, Department of Health Promotion, Kyushu Dental University, Kitakyushu, Fukuoka, Japan.,Division of Oral and Maxillofacial Surgery, Department of Science of Physical Function, Kyushu Dental University, Kitakyushu, Fukuoka, Japan
| | - Wataru Ariyoshi
- Division of Infections and Molecular Biology, Department of Health Promotion, Kyushu Dental University, Kitakyushu, Fukuoka, Japan
| | - Toshinori Okinaga
- Division of Infections and Molecular Biology, Department of Health Promotion, Kyushu Dental University, Kitakyushu, Fukuoka, Japan
| | - Jun Takeuchi
- Pharmaceuticals Information Group, Seikagaku Corporation, Tokyo, Japan
| | - Sho Mitsugi
- Division of Oral and Maxillofacial Surgery, Department of Science of Physical Function, Kyushu Dental University, Kitakyushu, Fukuoka, Japan
| | - Kazuhiro Tominaga
- Division of Oral and Maxillofacial Surgery, Department of Science of Physical Function, Kyushu Dental University, Kitakyushu, Fukuoka, Japan
| | - Tatsuji Nishihara
- Division of Infections and Molecular Biology, Department of Health Promotion, Kyushu Dental University, Kitakyushu, Fukuoka, Japan
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Matrix Metalloproteinases in the Interstitial Space. Protein Sci 2016. [DOI: 10.1201/9781315374307-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
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Tomonaga A, Watanabe K, Fukagawa M, Suzuki A, Kurokawa M, Nagaoka I. Evaluation of the effect of N-acetyl-glucosamine administration on biomarkers for cartilage metabolism in healthy individuals without symptoms of arthritis: A randomized double-blind placebo-controlled clinical study. Exp Ther Med 2016; 12:1481-1489. [PMID: 27588069 DOI: 10.3892/etm.2016.3480] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2015] [Accepted: 05/16/2016] [Indexed: 11/06/2022] Open
Abstract
The present study aimed to evaluate the effect of N-acetyl-glucosamine (GlcNAc) on the joint health of healthy individuals without arthritic symptoms. A randomized double-blind placebo-controlled clinical trial was performed to investigate the effect of oral administration of a GlcNAc-containing test supplement (low dose, 500 mg/day and high dose, 1,000 mg/day) on cartilage metabolism in healthy individuals with a mean age of 48.6±1.3 years (range, 23-64 years) by analyzing the ratio of type II collagen degradation to type II collagen synthesis using type II collagen degradation (C2C) and synthesis (PIICP) markers. The results indicated that the changes in C2C/PIICP ratios from the baseline were suppressed in the treated with low and high doses of GlcNAc, compared with the placebo group at week 16 during intervention. To further elucidate the effect of GlcNAc, subjects with impaired cartilage metabolism were evaluated. Notably, the changes in the C2C/PIICP ratios were markedly suppressed in the groups treated with low and high doses of GlcNAc at week 16. Finally, to exclude the effect of heavy body weight on joint loading, subjects weighing <70 kg with impaired cartilage metabolism were analyzed. Notably, the changes in the C2C/PIICP ratios were suppressed in the groups treated with low and high doses of GlcNAc at weeks 12 and 16. No test supplement-related adverse events were observed during or following the intervention. Together, these observations suggest that oral administration of GlcNAc at doses of 500 mg and 1,000 mg/day exhibits a chondroprotective effect on healthy individuals by reducing the C2C/PIICP ratio (relatively decreasing type II collagen degradation and increasing type II collagen synthesis) without any apparent adverse effects.
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Affiliation(s)
| | - Keita Watanabe
- Kitashinyokohama Orthopedic Surgery, Kanagawa 222-0059, Japan
| | | | | | | | - Isao Nagaoka
- Department of Host Defense and Biochemical Research, Graduate School of Medicine, Juntendo University, Tokyo 113-8421, Japan
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Dasa V, DeKoven M, Sun K, Scott A, Lim S. Clinical and cost outcomes from different hyaluronic acid treatments in patients with knee osteoarthritis: evidence from a US health plan claims database. Drugs Context 2016; 5:212296. [PMID: 27403194 PMCID: PMC4924978 DOI: 10.7573/dic.212296] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2016] [Indexed: 12/18/2022] Open
Abstract
Background: Intra-articular injection of hyaluronic acid (HA) for knee osteoarthritis (OA) effectively reduces pain and delays total knee replacement (TKR) surgery; however, little is known about relative differences in clinical and cost outcomes among different HA products. Objective: To compare disease-specific costs and risk of TKR among patients receiving different HA treatments in a commercially insured cohort of patients with knee OA in the USA. Method: Retrospective analyses using IMS Health’s PharMetrics Plus Health Plan Claims Database were conducted by identifying knee OA patients with claims indicating initiation of HA treatment at an ‘index date’ during the selection period (2007–2010). Patients were required to be continuously enrolled in the database for 12 months preindex to 36 months postindex. A generalized linear model (GLM) with a gamma distribution and log-link function was used to model aggregate patient-based changes in disease-specific costs. A Cox proportional hazards model (PHM) was used to model the risk of TKR. Both multivariate models included covariates such as age, gender, comorbidities, and preindex healthcare costs. Results: 50,389 patients with HA treatment for knee OA were identified. 18,217 (36.2%) patients were treated with HA products indicated for five injections per treatment course (Supartz and Hyalgan). The remainder were treated with HA products indicated for fewer than five injections per treatment course, with 20,518 patients (40.7%) receiving Synvisc; 6,263 (12.4%), Euflexxa; and 5,391 (10.7%), Orthovisc. Synvisc- and Orthovisc-injected patients had greater disease-specific costs compared to Supartz/Hyalgan (9.0%, p<0.0001 and 6.8%, p=0.0050, respectively). Hazard ratios (HRs) showed a significantly higher risk of TKR for patients receiving Synvisc compared to Supartz/Hyalgan (HR=1.069, p=0.0009). Patients treated with Supartz/Hyalgan, Euflexxa, and Orthovisc had longer delays to TKR than those treated with Synvisc. Conclusion: Analysis of administrative claims data provides real-world evidence that meaningful differences exist among some HA products in disease-specific cost and time to knee replacement surgery.
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Affiliation(s)
- Vinod Dasa
- Louisiana State University, New Orleans, LA, USA
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Hyaluronic Acid Suppresses the Expression of Metalloproteinases in Osteoarthritic Cartilage Stimulated Simultaneously by Interleukin 1β and Mechanical Load. PLoS One 2016; 11:e0150020. [PMID: 26934732 PMCID: PMC4774918 DOI: 10.1371/journal.pone.0150020] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2015] [Accepted: 02/08/2016] [Indexed: 12/05/2022] Open
Abstract
Purpose In patients with osteoarthritis (OA), intraarticular injection of hyaluronic acid (HA) frequently results in reduced pain and improved function for prolonged periods of time, i.e. more than 6 months. However, the mechanisms underlying these effects are not fully understood. Our underlying hypothesis is that HA modifies the enzymatic breakdown of joint tissues. Methods To test this hypothesis, we examined osteochondral cylinders from 12 OA patients. In a bioreactor, these samples were stimulated by interleukin 1β (Il1ß) (2 ng/ml) plus mechanical load (2.0 Mpa at 0.5 Hz horizontal and 0.1 Hz vertical rotation), thus the experimental setup recapitulated both catabolic and anabolic clues of the OA joint. Results Upon addition of HA at either 1 or 3 mg/ml, we observed a significant suppression of expression of metalloproteinase (MMP)-13. A more detailed analysis based on the Kellgren and Lawrence (K&L) OA grade, showed a much greater degree of suppression of MMP-13 expression in grade IV as compared to grade II OA. In contrast to the observed MMP-13 suppression, treatment with HA resulted in a suppression of MMP-1 expression only at 1 mg/ml HA, while MMP-2 expression was not significantly affected by either HA concentration. Conclusion Together, these data suggest that under concurrent catabolic and anabolic stimulation, HA exhibits a pronounced suppressive effect on MMP-13. In the long-run these findings may benefit the development of treatment strategies aimed at blocking tissue degradation in OA patients.
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