Hyaluronan-Binding Protein Involved in Hyaluronan Depolymerization Is Up-Regulated and Involved in Hyaluronan Degradation in Human Osteoarthritic Cartilage

Abstract

Hyaluronan (HA)-binding protein involved in HA depolymerization (HYBID), also called cell migration-inducing protein (CEMIP; alias KIAA1199), plays a key role in the degradation of HA in skin and arthritic synovial fibroblasts, but its functions in osteoarthritic (OA) cartilage remain elusive. Here, we investigated the expression and roles of HYBID in human OA cartilage. HYBID was highly expressed by chondrocytes in the HA-depleted area of OA cartilage, and HYBID immunoreactivity was correlated with Mankin score, the histopathologic severity of OA lesions of cartilage. Real-time quantitative PCR indicated that HYBID expression was significantly higher in OA cartilage than in control cartilage. In addition, OA chondrocytes exhibited HA-degrading activity, which was abolished by knock-down of HYBID by siRNAs. Although OA chondrocytes also expressed certain levels of hyaluronidases 1 and 2 and CD44, knock-down of these molecules exhibited negligible effects on HA degradation. Double immunostaining of HYBID and clathrin heavy chain revealed that HYBID was localized in the clathrin-coated vesicles, and HA was endocytosed within the vesicles of OA chondrocytes. Among eight factors including cytokines and growth factors examined, only tumor necrosis factor α stimulated OA chondrocytes to overexpress HYBID. These data are the first to demonstrate that HYBID is up-regulated in OA cartilage, and suggest that tumor necrosis factor α-stimulated HYBID plays a role in HA degradation in OA cartilage.

CEMIP (KIAA1199) induces a fibrosis-like process in osteoarthritic chondrocytes

“…These data suggest that CEMIP could have a significant role in the molecular disturbance encountered at an early stage of the disease. In accordance, very recently Shimizu et al 35 , showed that CEMIP expression correlated with Mankin score of OA patients.…”

Induction of CEMIP in Chondrocytes by Inflammatory Cytokines: Underlying Mechanisms and Potential Involvement in Osteoarthritis

“…Therefore, we explored the mechanism of CEMIP regulation in chondrocytic cells. Shimizu et al reported that CEMIP expression in OA chondrocytes was induced by TNFα, but not by TGF-β1, IL-1α, histamine, insulin-like growth factor (IGF)-1, vascular endothelial growth factor (VEGF)-165, basic fibroblast growth factor (bFGF), or prostaglandin E2 (PGE2) [20]. Interestingly, our results demonstrated that IL-1β induced CEMIP mRNA expression in OUMS-27 cells.…”

“…Previous studies have demonstrated that HA synthesis by HAS (hyaluronan synthase) was involved in OA development [19]. HYAL-1, HYAL-2, and CD44 were found to be increased in OA chondrocytes compared to normal cartilage, but their gene knockdown did not have a significant effect on HA degradation [20]. These data suggested that CEMIP might be associated with HA metabolism in OA cartilage.…”

The Pancreatic Cancer-Initiating Cell Marker CD44v6 Affects Transcription, Translation, and Signaling: Consequences for Exosome Composition and Delivery

“…This was seen in cells but preferentially in TEX. Additional proteins selectively or preferentially coimmunoprecipitating with CD44v6 that could assist integrin activation are CLTC (clathrin heavy chain 1) and CSPG4 (chondroitin sulfate proteoglycan 4) [57, 58]. CD44v6 also associates with LGR5/LGR6, which supports Wnt binding and downstream signaling activation [12, 36].…”