Aggrecan degradation in human articular cartilage explants is mediated by both ADAMTS-4 and ADAMTS-5.
Ruo-Hua Song,Micky D. Tortorella,Anne-Marie Malfait,James T. Alston,Zhiyong Yang,Elizabeth C. Arner,David W. Griggs +6 more
TLDR
Despite the apparent dominant role of ADAMTS-5 in genetically modified mice, the data suggest that both ADAMts-4 and ADAM TS-5 contribute to the structural damage that characterizes human OA.Abstract:
Objective
Recent published studies have shown that cartilage from ADAMTS-5–knockout mice, but not ADAMTS-4– or ADAMTS-1–knockout mice, is significantly protected from degradation. The present study was undertaken to evaluate the respective roles of these enzymes in human cartilage breakdown, using a small interfering RNA (siRNA) approach to assess the effects of inhibition of each enzyme in normal and osteoarthritic (OA) explants.
Methods
The activities of siRNA specifically targeting ADAMTS-1, -4, and -5 were assessed by transfection into primary human chondrocytes and cultured human cartilage explants. At 24 hours, a cytokine stimulus was applied to normal, but not OA, samples to initiate a catabolic response. At designated times, total RNA was isolated and gene expression was measured by quantitative real-time reverse transcription–polymerase chain reaction. Aggrecan release and aggrecanase-generated neoepitope formation were determined by dye binding analysis and Western blotting, respectively.
Results
Human chondrocytes and explants were efficiently transfected with siRNA that specifically decreased the expression of each targeted gene. Suppression of ADAMTS-4 and ADAMTS-5, individually or in combination, attenuated the degradation of aggrecan in cytokine-stimulated normal cartilage. A reduction in aggrecan degradation was also observed following siRNA-mediated knockdown of either gene in unstimulated OA cartilage. In contrast, knockdown of ADAMTS-1 failed to inhibit aggrecan loss.
Conclusion
Despite the apparent dominant role of ADAMTS-5 in genetically modified mice, our data suggest that both ADAMTS-4 and ADAMTS-5 contribute to the structural damage that characterizes human OA.read more
Citations
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Inflammation in osteoarthritis
Mary B. Goldring,Miguel Otero +1 more
TL;DR: This review focuses on the novel stress-induced and proinflammatory mechanisms underlying the pathogenesis of osteoarthritis, with particular attention to the role of synovitis and the contributions of other joint tissues to cellular events that lead to the onset and progression of the disease and irreversible cartilage damage.
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Chondrocyte hypertrophy and osteoarthritis: role in initiation and progression of cartilage degeneration?
TL;DR: It is proposed that altered chondrocyte behavior and concomitant cartilage degradation result in a disease-amplifying loop, leading to a mixture of disease stages and cellular responses within an OA joint, which might be a therapeutic target to slow down further OA progression.
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Proteases involved in cartilage matrix degradation in osteoarthritis
Linda Troeberg,Hideaki Nagase +1 more
TL;DR: Recent advances in current understanding of the mechanisms regulating expression of these key enzymes are discussed, as well as reviewing the roles of other proteinases in cartilage destruction.
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Hypoxia-inducible factor-2α is a catabolic regulator of osteoarthritic cartilage destruction
Siyoung Yang,Jonghwan Kim,Je-Hwang Ryu,Hwanhee Oh,Churl-Hong Chun,Byoung Ju Kim,Byoung-Hyun Min,Jang-Soo Chun +7 more
TL;DR: It is demonstrated that HIF-2α causes cartilage destruction by regulating crucial catabolic genes in the osteoarthritic process by inducing the expression in chondrocytes of genes encoding catabolic factors.
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The ADAMTS (A Disintegrin and Metalloproteinase with Thrombospondin motifs) family.
TL;DR: Focusing primarily on the aggrecanases and proteoglycanases, a perspective on the evolution of the ADAMTS family, their links with developmental and disease mechanisms, and key questions for the future are provided.
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Deletion of active ADAMTS5 prevents cartilage degradation in a murine model of osteoarthritis
S.S. Glasson,Roger Askew,Barbara Sheppard,Brenda A. Carito,Tracey Blanchet,Hak-Ling Ma,Carl R. Flannery,Peluso Diane,Kim Kanki,Zhiyong Yang,Manas K. Majumdar,Elisabeth A. Morris +11 more
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