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

Abstract

IntroductionWnt ligands bind to low-density lipoprotein receptor–related protein (LRP) 5 or 6, triggering a cascade of downstream events that include β-catenin signaling. Here we explored the roles of LRP5 in interleukin 1β (IL-1β)- or Wnt-mediated osteoarthritic (OA) cartilage destruction in mice.MethodsThe 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 (Lrp5fl/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-1β or Wnt proteins.ResultsIL-1β treatment increased the expression of LRP5 (but not LRP6) via JNK and NF-κB signaling. LRP5 was upregulated in human and mouse OA cartilage, and Lrp5 deficiency in mice inhibited cartilage destruction. Treatment with IL-1β 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 β-catenin. Moreover, Lrp5-/- and Lrp5fl/fl;Col2a1-cre mice exhibited decreased cartilage destruction (and related changes in gene expression) in response to experimental OA.ConclusionsOur findings indicate that LRP5 (but not LRP6) plays an essential role in Wnt/β-catenin-signaling-mediated OA cartilage destruction in part by regulating the expression levels of type II collagen, MMP3, and MMP13.

Genome-wide DNA methylation profiling of articular cartilage reveals significant epigenetic alterations in Kashin-Beck disease and osteoarthritis

“…Both LRP1 and LRP5 involved in OA chondrocyte physiopathology 28,29 . LRP5 can govern Wnt-mediated osteoarthritic cartilage destruction, whereas LRP1-mediated endocytosis is capable of regulating extracellular activity of ADAMTS-5 in articular cartilage 28,29 . Epigenetic alterations of apolipoproteins may also involve in the cartilage destruction of KBD.…”

CD4 T-cell transcriptome analysis reveals aberrant regulation of STAT3 and Wnt signaling pathways in rheumatoid arthritis: evidence from a case–control study

“…The synovial fluid T cells from the patients with RA were resistant to FasL-induced apoptosis [ 29 ]. Furthermore, accumulated evidence suggested that the Wnt signaling pathway plays an important role in FLS activation, bone resorption, and joint destruction in RA pathogenesis [ 30 - 34 ]. In the context of Wnt signaling in T-cell activation, it has been reported that activation of Wnt signaling in CD4 + CD25 + regulatory T (Treg) cells increased the survival of Treg cells and induced an anergic phenotype in CD4 + CD25 − effector T cells [ 35 , 36 ].…”

Recent advances in the understanding of molecular mechanisms of cartilage degeneration, synovitis and subchondral bone changes in osteoarthritis

“…Recent findings implied that β-catenin was upregulated in articular cartilage tissue derived from patients with OA (34). Moreover, protein secreted Frizzledrelated protein (Sfrp)3, a secreted negative regulatory factor of Wnt signaling, and mutations of the Frizzledrelated protein (FrzB) gene can increase susceptibility to OA (35).…”