Cholesterol-induced LRP3 downregulation promotes cartilage degeneration in osteoarthritis by targeting Syndecan-4

Abstract

Emerging evidence suggests that osteoarthritis is associated with high cholesterol levels in some osteoarthritis patients. However, the specific mechanism under this metabolic osteoarthritis phenotype remains unclear. We find that cholesterol metabolism-related gene, LRP3 (low-density lipoprotein receptor-related protein 3) is significantly reduced in high-cholesterol diet mouse’s cartilage. By using Lrp3−/− mice in vivo and LRP3 lentiviral-transduced chondrocytes in vitro, we identify that LRP3 positively regulate chondrocyte extracellular matrix metabolism, and its deficiency aggravate the degeneration of cartilage. Regardless of diet, LRP3 overexpression in cartilage attenuate anterior cruciate ligament transection induced osteoarthritis progression in rats and Lrp3 knockout-induced osteoarthritis progression in mice. LRP3 knockdown upregulate syndecan-4 by activating the Ras signaling pathway. We identify syndecan-4 as a downstream molecular target of LRP3 in osteoarthritis pathogenesis. These findings suggest that cholesterol-LRP3- syndecan-4 axis plays critical roles in osteoarthritis development, and LRP3 gene therapy may provide a therapeutic regimen for osteoarthritis treatment.

Reprogramming of Mitochondrial Respiratory Chain Complex by Targeting SIRT3‐COX4I2 Axis Attenuates Osteoarthritis Progression

“…Lipid and cholesterol accu-mulation are proposed as the contributing risk factors for OA development. [46] Similar to our findings, SIRT3 exerts protective actions on articular cartilage in aging-related OA model. [12] Our gain-of-function experiments further suggested that activation of SIRT3 recouples the mitochondrial redox balance, a notable feature in OA, [47] to attenuate chondrocytes injury.…”

Genetics may affect the risk of undergoing surgery for rhizarthrosis

“…MVK is involved in regulation of cholesterol and isoprene biosynthesis, 35 and the identified variant in MVK was positively associated with cholesterol levels in publicly available datasets. The fact that the variant is suggestively protective (OR = 0.79) while being positively associated with cholesterol levels may seem counterintuitive given the plausible negative relationship between cholesterol and osteoarthritis 36,37 . However, since none of the identified variants reached genome‐wide significance or have been examined for causality, further speculation about the pathophysiological relevance of the variants and their related genes is currently unwarranted.…”

Interleukins, growth factors, and transcription factors are key targets for gene therapy in osteoarthritis: A scoping review

“…Low-density lipoprotein (LDL) receptor-related proteins (LRPs) play an important part in the regulation of cholesterol metabolism and have recently been shown to be involved in the onset and progression of OA ( 88 ). Cao et al investigated the potential role of LRP3 in OA pathogenesis and therapy ( 85 ). In TNF-α stimulated rat OA chondrocytes, lentiviral-mediated overexpression of Lrp3 induced the expression of the anabolic genes COL2A1, ACAN, and SOX9, and restored expression of proteoglycan and GAG.…”