Divergent chondro/osteogenic transduction laws of fibrocartilage stem cell drive temporomandibular joint osteoarthritis in growing mice
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Abstract The anterior disc displacement (ADD) leads to temporomandibular joint osteoarthritis (TMJOA) and mandibular growth retardation in adolescent. To investigate the potential functional role of fibrocartilage stem cells (FCSCs) during the process, a surgical ADD-TMJOA mouse model was established. From 1 week after model generation, ADD mice exhibited aggravated mandibular growth retardation with osteoarthritis (OA)-like joint cartilage degeneration, manifesting with impaired chondrogenic differentiation and loss of subchondral bone homeostasis. Lineage tracing using Gli1-CreER + ; Tm fl/− mice and Sox9-CreER + ; Tm fl/− mice showed that ADD interfered the chondrogenic capacity of Gli1 + FCSCs as well as osteogenic differentiation of Sox9 + lineage, mainly in the middle zone of TMJ cartilage. Then, a surgically induced disc reposition (DR) mouse model was generated. The inhibited FCSCs capacity were significantly alleviated by DR treatment in ADD mice. And both the ADD mice and adolescent ADD patients had significantly relieved OA phenotype and improved condylar growth after DR treatment. In conclusion, ADD-TMJOA leads to impaired chondrogenic progenitor capacity and osteogenesis differentiation of FCSCs lineage, results in cartilage degeneration and loss of subchondral bone homeostasis, finally causes TMJ growth retardation. DR at an early stage could significantly alleviate cartilage degeneration and restore TMJ cartilage growth potential.Keywords:
Fibrocartilage
Chondrogenesis
SOX9
Subchondral bone
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Chondrogenesis
Fibrocartilage
Hyaline cartilage
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Microfracture, a common procedure for treatment of cartilage injury, induces fibrocartilage repair by recruiting bone marrow derived mesenchymal stem cells (MSC) to the site of cartilage injury. However, fibrocartilage is inferior biomechanically to hyaline cartilage. SRY-type high-mobility group box-9 (SOX9) is a master regulator of chondrogenesis by promoting proliferation and differentiation of MSC into chondrocytes. In this study we aimed to test the therapeutic potential of cell penetrating recombinant SOX9 protein in regeneration of hyaline cartilage in situ at the site of cartilage injury. We generated a recombinant SOX9 protein which was fused with super positively charged green fluorescence protein (GFP) (scSOX9) to facilitate cell penetration. scSOX9 was able to induce chondrogenesis of bone marrow derived MSC in vitro. In a rabbit cartilage injury model, scSOX9 in combination with microfracture significantly improved quality of repaired cartilage as shown by macroscopic appearance. Histological analysis revealed that the reparative tissue induced by microfracture with scSOX9 had features of hyaline cartilage; and collagen type II to type I ratio was similar to that in normal cartilage. This short term in vivo study demonstrated that when administered at the site of microfracture, scSOX9 was able to induce reparative tissue with features of hyaline cartilage.
Fibrocartilage
Hyaline cartilage
Chondrogenesis
SOX9
Aggrecan
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Chondrogenesis
SOX9
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In the embryonic development of skeletal elements, cartilage appears to form through the cellular condensation at a particular region within mesenchymal tissues. During this process, cartilage stem cells (or chondroprogenitor cells) pass through several distinct cellular stages, which are regulated by a variety of growth and differentiation factors. In contrast to embryos, chondrogenesis rarely occurs in vivo after birth, except in the process of fracture healing or, to a limited extent, repair of articular cartilage. Full-thickness defects that penetrate articular cartilage are filled with fibrous tissue, fibrocartilage, or rarely with hyaline cartilage. Here we discuss ongoing attempts to induce chondrogenesis for the future therapeutic applications.
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Hyaline cartilage
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Fibrocartilage
Chondrogenesis
Hyaline cartilage
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Osteoarthritis is a degenerative disease mainly caused by aging, although in younger patients (aged 25 – 50) it can be a consequence of sports-related injuries or trauma. This results in early osteoarthritis with subsequent changes in cartilage extracellular matrix. Cell-based tissue engineering approaches using mesenchymal stem cells (MSCs) are an ideal cell type for the treatment of early osteoarthritc defects. Our group has demonstrated in a clinical study, that interleukin-1β (IL-1β) was expressed in cartilage plugs from patients with early osteoarthritis. In vitro studies have shown that IL-1β inhibits cartilage formation in chondrocytes or MSCs undergoing chondrogenesis. However, these studies show complete inhibition of tissue formation, whereas in the context of early osteoarthritis, cartilage extracellular matrix remains around the defect site. Thus, the present study sought to develop a model mimicking early osteoarthritis using MSCs. Method Human MSCs (Male donors; aged 18–60 years, n = 6) were...
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Regeneration of human cartilage is inherently inefficient. Current cell-based approaches for cartilage repair, including autologous chondrocytes, are limited by the paucity of cells, associated donor site morbidity, and generation of functionally inferior fibrocartilage rather than articular cartilage. Upon investigating the role of collagen VI (Col VI), a major component of the chondrocyte pericellular matrix (PCM), we observe that soluble Col VI stimulates chondrocyte proliferation. Interestingly, both adult and osteoarthritis chondrocytes respond to soluble Col VI in a similar manner. The proliferative effect is, however, strictly due to the soluble Col VI as no proliferation is observed upon exposure of chondrocytes to immobilized Col VI. Upon short Col VI treatment in 2D monolayer culture, chondrocytes maintain high expression of characteristic chondrocyte markers like Col2a1, agc, and Sox9 whereas the expression of the fibrocartilage marker Collagen I (Col I) and of the hypertrophy marker Collagen X (Col X) is minimal. Additionally, Col VI-expanded chondrocytes show a similar potential to untreated chondrocytes in engineering cartilage in 3D biomimetic hydrogel constructs. Our study has, therefore, identified soluble Col VI as a biologic that can be useful for the expansion and utilization of scarce sources of chondrocytes, potentially for autologous chondrocyte implantation. Additionally, our results underscore the importance of further investigating the changes in chondrocyte PCM with age and disease and the subsequent effects on chondrocyte growth and function.
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Chronic inflammation is one of the major causes of cartilage destruction in osteoarthritis. During the progression of osteoarthritis,extracellular matrix of cartilage( ECM) is actively remodeled by chondrocytes in inflammatory conditions. This alteration of ECM,in turn,changes the biomechanical environment of chondrocytes,which further drives the progression of the disease in the presence of inflammation. The changes in ECM composition and structure also prevent participation of mesenchymal stem cells in the repair process by inhibiting their chondrogenic differentiation.
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Background: Current decisions on cellular therapies for osteoarthritis are based primarily on clinical experience or on assumptions about preferred cell sourcing. They have not been informed by rigorous standardized measurements of the chondrogenic connective-tissue progenitors (CTP-Cs) or their intrinsic diversity of chondrogenic potential. The goal of this study was to quantitatively define the CTP-Cs resident in cartilage of different grades of osteoarthritis and to compare their concentration, prevalence, and biological potential. Methods: Twenty-three patients who had varus malalignment of the knee and were scheduled to undergo elective total knee arthroplasty for idiopathic osteoarthritis and who had grade 1-2 osteoarthritis on the lateral femoral condyle and grade 3-4 osteoarthritis on the medial femoral condyle were recruited for study of the cartilage removed during surgery. CTP-Cs were assayed by a standardized colony-forming-unit assay using automated image-analysis software based on ASTM standard test method F2944-12. Results: Cell concentration was significantly greater (p < 0.001) in grade 3-4 cartilage than in grade 1-2 cartilage. The prevalence of CTP-Cs varied widely, but it trended lower in grade 3-4 cartilage than in grade 1-2 samples (p = 0.078). The biological performance of CTP-Cs from grade 1-2 and grade 3-4 cartilage was comparable. Increased cell concentration was a significant predictor of decreased CTP-C prevalence (p = 0.002). Conclusions: Although grade 3-4 cartilage showed fewer CTP-Cs than grade 1-2 cartilage, the range of biological performance was comparable, which suggests that either may be used as a source for potent CTP-Cs. However, the biological reason for the heterogeneity of CTP-Cs in cartilage and the biological implications of that heterogeneity are not well understood and require further study. Clinical Relevance: In order to improve the efficacy of cartilage cell therapy procedures, it is key to characterize the quality and quantity of the cells and progenitors being administered. Additionally, understanding the heterogeneity in order to select appropriate subsets of populations will improve the rigor of decisions concerning cell sourcing and targeting for pharmacological and cellular therapies.
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Knee cartilage
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