Expression and regulation of recently discovered hyaluronidases, HYBID and TMEM2, in chondrocytes from knee osteoarthritic cartilage

Destruction of articular cartilage in osteoarthritis (OA) is initiated by depletion of the hyaluronan (HA)-aggrecan network, followed by degradation of the collagen fibrils. Previously, we reported the implications of HA-binding protein involved in HA depolymerization (HYBID), alias cell migration-inducing protein (CEMIP) and KIAA1199, for HA degradation. However, transmembrane protein 2 (TMEM2), which is similar to 50% homologous to HYBID, was discovered as another hyaluronidase, but their expression and regulation by OA chondrocytes remain elusive. Here we report that the absolute mRNA copy numbers of HYBID are significantly (7.1-fold) higher in OA cartilage than normal cartilage, whereas TMEM2 levels are not different between the groups. HA-degrading activity of cultured OA chondrocytes disappeared by siRNA-mediated knockdown of HYBID, but not TMEM2. HYBID expression was significantly up-regulated by treatment with interleukin-6 (IL-6) or tumor necrosis factor-alpha (TNF-alpha) and additively increased by the combined treatment. No significant changes in the TMEM2 expression were seen by the factors examined. IL-1 alpha remarkably enhanced IL-6 production and increased HYBID expression when soluble IL-6 receptor was supplemented. These results demonstrate that in stark contrast to the constitutive expression of TMEM2 and its negligible HA-degrading activity, HYBID is overexpressed in OA cartilage and up-regulated by IL-6 and TNF-alpha in OA chondrocytes.

Automated summary

Destruction of articular cartilage in osteoarthritis is caused by the loss of the hyaluronan-aggrecan network and degradation of collagen fibrils. This study found that the HA-binding protein HYBID is overexpressed in osteoarthritis cartilage, and its expression is up-regulated by interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha). In contrast, the expression of the transmembrane protein TMEM2 is not significantly different in osteoarthritis cartilage. HYBID plays a role in HA degradation, while TMEM2 has negligible HA-degrading activity.