Low-density lipoprotein receptor-related protein 5 governs Wnt-mediated osteoarthritic cartilage destruction

Abstract

Introduction: Wnt ligands bind to low-density lipoprotein receptor-related protein (LRP) 5 or 6, triggering a cascade of downstream events that include beta-catenin signaling. Here we explored the roles of LRP5 in interleukin 1 beta (IL-1 beta)-or Wnt-mediated osteoarthritic (OA) cartilage destruction in mice. Methods: The expression levels of LRP5, type II collagen, and catabolic factors were determined in mouse articular chondrocytes, human OA cartilage, and mouse experimental OA cartilage. Experimental OA in wild-type, Lrp5 total knockout (Lrp5(-/-)) and chondrocyte-specific knockout (Lrp5(fl/fl); Col2a1-cre) mice was caused by aging, destabilization of the medial meniscus (DMM), or intra-articular injection of collagenase. The role of LRP5 was confirmed in vitro by small interfering RNA-mediated knockdown of Lrp5 or in Lrp5(-/-) cells treated with IL-1 beta or Wnt proteins. Results: IL-1 beta treatment increased the expression of LRP5 (but not LRP6) via JNK and NF-kappa B signaling. LRP5 was upregulated in human and mouse OA cartilage, and Lrp5 deficiency in mice inhibited cartilage destruction. Treatment with IL-1 beta or Wnt decreased the level of Col2a1 and increased those of Mmp3 or Mmp13, whereas Lrp5 knockdown ameliorated these effects. In addition, we found that the functions of LRP5 in arthritic cartilage were subject to transcriptional activation by beta-catenin. Moreover, Lrp5(-/-) and Lrp5(fl/fl); Col2a1-cre mice exhibited decreased cartilage destruction (and related changes in gene expression) in response to experimental OA. Conclusions: Our findings indicate that LRP5 (but not LRP6) plays an essential role in Wnt/beta-catenin-signaling-mediated OA cartilage destruction in part by regulating the expression levels of type II collagen, MMP3, and MMP13.