In OA, cartilage destruction is initiated by defects in joint biomechanics in conjunction with predisposing factors, new post leading to an imbalance of anabolic and catabolic factors. Various biochemical pathways are modulated, resulting in the insufficient synthesis of cartilage matrix by chondrocytes, increased numbers of apoptotic chondrocytes and degradation of the ECM due to increased production of MMPs and ADAMTS. In this study, we demonstrate that Lrp5 is a crucial catabolic regulator of Wnt B catenin sig naling mediated OA cartilage destruction. We first ob served upregulation of LRP5 in human and experimental mouse OA cartilage samples. Our evaluation of the spe cific functions of LRP5 in OA pathogenesis further re vealed that Lrp5 deficiency in mice exerted a protective effect against OA pathogenesis.

Our results additionally suggest that the catabolic regulation of LRP5 is associated with its capacity to initiate Wnt mediated Inhibitors,Modulators,Libraries expression of catabolic factors, such as MMP3 and MMP13, and decrease the anabolic factor, type II collagen. LRP5 and LRP6 are paralogs that are 70% identical, and both are capable of stimulating the Wnt B catenin signaling pathway. Even though they Inhibitors,Modulators,Libraries have redundant and overlapping functions, several previous re ports have suggested that LRP5 and LRP6 also play dis tinct roles due to their differences in tissue distribution and ligand affinities. For example, a loss of function mutation in Lrp5 causes OPPG syndrome, a disorder involving low bone mass, whereas Lrp6 de ficiency in mice is an embryonic lethal disorder, and a heterozygous loss of function mutation in Lrp6 is associated with decreased B catenin signaling within articular cartilage and increased degen erative joint disease after ligament and meniscus injury.

These previous findings indicate that the specific re ceptors for LRP5 and LRP6 control different functions, presumably by interacting with distinct ligands of the Wnt family. In an effort to further confirm the catabolic regula tion of Lrp5, we examined the expression levels of Lrp5 and Lrp6 in differentiating chondrocytes, human OA Inhibitors,Modulators,Libraries car tilage and cartilage samples from various experimental mouse models of OA. We observed distinct expression patterns for Lrp5 and Lrp6 during chondrogenesis and the IL 1B induced dedifferentiation of chondrocytes.

LRP5 ex pression in OA cartilage was increased, consistent with previous reports, Inhibitors,Modulators,Libraries whereas LRP6 expression was unaltered. These findings provide additional evidence that LRP5 and LRP6 have distinct expression patterns and may play different roles in OA cartilage destruction. Previous Inhibitors,Modulators,Libraries studies have suggested that LRP5 may con tribute to OA pathogenesis, but its function in OA carti lage destruction has been the subject of some controversy. LRP5 expression was found to be significantly upregulated in human OA cartilage, and a cohort study suggested that haplotypes of the Lrp5 gene are selleckchem risk factors for OA.