However, we found that the inhibitory effect of Lrp5 defi ciency on DMM surgery induced OA cartilage de gradation in Lrp5fl fl.Col2a1 cre mice was consistent with the results from selleck chem inhibitor total Lrp5 mice. These data indicate that LRP5 has catabolic effects during OA cartilage degradation. In the current study, we used recombinant Wnt3a and Wnt7a as representative ligands of the canonical Wnt B catenin signaling pathway to evaluate the function of Lrp5. We did not e amine the upregulation of Wnt molecules in the OA cartilage of our e perimental sys tems, but Wnt3a is known to activate the canonical Wnt pathway and stimulate the e pression of Mmp13 and Adamts4 in mouse chondrocytes. We previously showed that IL 1B upregulates Wnt7a e pression, thereby inhibiting type II collagen e pression in chon drocytes.
Moreover, we found that the e pression levels of various Wnt and Fz receptor isotypes were reg ulated by IL 1B. In this study, we found that stimula tion of canonical Wnt signaling via Wnt3a treatment caused upregulation of Mmp13 in mouse articular chon drocytes, whereas Wnt7a treatment decreased Col2a1 e pression and increased Mmp3 and Mmp13 e pression. Our observation that Wnt7a and IL 1B have similar effects on gene e pression in chondrocytes is consistent with a previous report in which we showed that IL 1B induced upregulation of Wnt7a in articular chon drocytes. Notably, however, the Wnt mediated regulation of Col2a1, Mmp3 and Mmp13 were abrogated in primary cultured chondrocytes from Lrp5 mice.
On the basis of these data, we speculate that catabolic gene e pression is convergently modulated by IL 1B in chondrocytes, with IL 1B mediated Wnt7a and Lrp5 e pression triggering downregulation Batimastat of Col2a1 and upregulation of Mmp3 and Mmp13, potentially contributing to the IL 1B induced activation of B catenin. The catabolic effects of LRP5 may be attributable to its capacity to upregulate Mmp3 and Mmp13, which encode proteins that are capable of degrading a variety of ECM components during the arthritic process. Moreover, genetic studies in mice have clearly demonstrated that MMP3 and MMP13 play crucial roles in OA pathogenesis. We observed that Wnt3a induced the e pression of Adamts4. Notably, however, Adamts4 deficiency in mice did not show protective effects against OA cartilage destruction, whereas Mmp13 KO mice are resistant to OA cartilage erosion.
Therefore, the capacity of LRP5 to facilitate the Wnt induced e pression of MMP13 appears to be associated with the positive effects of LRP5 on OA cartilage destruction. The selleck bio LRP5 induced downregulation of the anabolic factor type II collagen in articular chondrocytes also contributes to cartilage de struction. We found that ectopic e pression of LRP5 induced the dedifferentiation of chondrocytes and was associated with the pathogenesis of OA. The apoptosis of chondrocytes, which is associated with the pathogenesis of OA, can be induced by a number of stimuli.