Abstract
ABSTRACTHyaluronan (HA) is an extracellular matrix (ECM) component of articular cartilage and has been used to treat patients with osteoarthritis (OA). A disintegrin and metalloproteinases with thrombospondin motifs (ADAMTSs) play an important role in cartilage degradation in OA. We have previously reported that ADAMTS4 and ADAMTS9 were induced by cytokine stimulation. However, the effect of HA on the cytokine‐inducible ADAMTS9 has never been investigated. Moreover, it is unclear whether HA protects cartilage by suppressing aggrecan degradation. Here, we examined the effects of HA on ADAMTS expression in vitro and on cartilage degradation in vivo. ADAMTS9 expression was higher than that of the other aggrecanases (ADAMTS4 and 5) in human chondrocytes, chondrocytic cells, and rat cartilage. ADAMTS4 and 9 mRNA levels were upregulated in cytokine‐stimulated chondrocytes and chondrocytic cells. Pre‐incubation with HA significantly inhibited ADAMTS9 mRNA expression in cytokine‐stimulated cells. In a rat OA model, Adamts5 and 9 mRNA levels were transiently increased after surgery; intra‐articular HA injections attenuated the induction of Adamts5 and 9 mRNA. HA also blocked aggrecan cleavage by aggrecanase in OA rats in a molecular size‐dependent manner. These results demonstrate that HA attenuates induced aggrecanases expression in OA and thereby protects articular cartilage degradation by this enzyme. Our findings provide insight into the molecular basis for the beneficial effects of HA in OA. © 2018 The Authors. Journal of Orthopaedic Research® Published by Wiley Periodicals, Inc. on behalf of Orthopaedic Research Society. J Orthop Res 36:3247–3255, 2018.
Highlights
Osteoarthritis (OA) is the most common type of cartilage disease and results from the degradation of extracellular matrix (ECM) in the joints
Co-treatment with IL1b and TNFa increased the mRNA levels of ADAMTS4 and 9 but not ADAMTS5 in NHAC-kn (Fig. 1A) and OUMS-27 (Fig. 1B) cells, with levels peaked at 6 h after the application
We have previously found that IL-1b and TNFa synergistically induced ADAMTS9.24 The qRTPCR Ct values for ADAMTS9 without cytokine stimulation were smaller than those for ADAMTS4 and 5 (Figs. 1A and 1B) in both types of cells
Summary
Osteoarthritis (OA) is the most common type of cartilage disease and results from the degradation of extracellular matrix (ECM) in the joints. Articular cartilage consists of chondrocytes and ECM molecules including aggrecan, type II, IX, and XI collagen, and hyaluronan (HA).[1] Aggrecan holds water in the matrix, allowing cartilage to resist mechanical forces[2]; it binds HA through its G1 domain[3] as part of a large complex consisting of 10– 100 aggrecan molecules per HA.[4] Aggrecan as well as collagen is degraded in OA cartilage[5] owing to the activity of matrix metallo proteinases and aggrecanases that target aggrecan cleavage sites.[6] Aggrecanase 1 and 2 ( known as ADAMTS4 and 5, respectively) cleave aggrecan at Glu373–Ala[374] in bovine nasal cartilage stimulated with interleukin (IL)-1.7,8 Other ADAMTSs (e.g., ADAMTS1 and 9) cleave aggrecan at this site.. We examined the effects of HA on the expression of ADAMTSs in cytokine-stimulated chondrocytes, as well as its protective function in knee cartilage in a rat OA model
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