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

Youngnim Shin,Je-Hwang Ryu,Ka Park,Suyeon Kim,Jang-Soo Chun,Yun Huh,Jeong-Tae Koh,Kieun Kim

doi:10.1186/ar4466

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.

Highlights

Wnt ligands bind to low-density lipoprotein receptor–related protein (LRP) 5 or 6, triggering a cascade of downstream events that include β-catenin signaling
Our findings indicate that LRP5 plays an essential role in Wnt/β-catenin signaling–mediated OA cartilage destruction by upregulating catabolic factors and downregulating the anabolic factor type II collagen
In pathogenic primary culture chondrocytes treated with interleukin 1β (IL-1β), Lrp5 expression was dramatically increased in a dose-dependent manner (Figure 1B) and a time-dependent manner (Figure 1C), whereas Lrp6 expression was constant (Figures 1B and 1C)

Summary

Introduction

Wnt ligands bind to low-density lipoprotein receptor–related protein (LRP) 5 or 6, triggering a cascade of downstream events that include β-catenin signaling. Osteoarthritis (OA), which is the most common chronic degenerative joint disorder worldwide, is characterized primarily by cartilage degradation and narrowing of the joint spaces [1] Both genetic and acquired factors, such as obesity, mechanical influences and age, are involved in the complex pathogenesis of OA, whereby cartilage homeostasis is disrupted by biophysical factors (for example, mechanical stress) and biochemical factors (for example, The Wnt signaling pathway is involved in cartilage development and homeostasis, as evidenced by the fact that a number of Wnt proteins and Frizzled (Fz) receptors are expressed in chondrocytes [4] and the synovial tissues of arthritic cartilage [5]. Additional work is clearly warranted to elucidate the molecular mechanisms underlying the LRP5-mediated regulation of OA pathogenesis

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