Abstract
In past years, the canonical Wnt/β-catenin signaling pathway has emerged as a critical regulator of cartilage development and homeostasis. FRZB, a soluble antagonist of Wnt signaling, has been studied in osteoarthritis (OA) animal models and OA patients as a modulator of Wnt signaling. We screened for FDA-approved drugs that induce FRZB expression and suppress Wnt/β-catenin signaling. We found that verapamil, a widely prescribed L-type calcium channel blocker, elevated FRZB expression and suppressed Wnt/β-catenin signaling in human OA chondrocytes. Expression and nuclear translocation of β-catenin was attenuated by verapamil in OA chondrocytes. Lack of the verapamil effects in LiCl-treated and FRZB-downregulated OA chondrocytes also suggested that verpamil suppressed Wnt signaling by inducing FRZB. Verapamil enhanced gene expressions of chondrogenic markers of ACAN encoding aggrecan, COL2A1 encoding collagen type II α1, and SOX9, and suppressed Wnt-responsive AXIN2 and MMP3 in human OA chondrocytes. Verapamil ameliorated Wnt3A-induced proteoglycan loss in chondrogenically differentiated ATDC5 cells. Verapamil inhibited hypertrophic differentiation of chondrocytes in the explant culture of mouse tibiae. Intraarticular injection of verapamil inhibited OA progression as well as nuclear localizations of β-catenin in a rat OA model. We propose that verapamil holds promise as a potent therapeutic agent for OA by upregulating FRZB and subsequently downregulating Wnt/β-catenin signaling.
Highlights
Osteoarthritis (OA) is a progressively degenerative joint disorder characterized by degradation of extracellular matrix (ECM) molecules, loss of articular cartilages, and formation of osteophytes
ECM including ACAN and collagens are degraded by matrix metalloproteinases (MMPs), aggrecanases (ADAMTSs), and other matrix proteases [2,3]
We found that verapamil suppressed the Wnt/b-catenin activity in a dosedependent manner (Figure 1B)
Summary
Osteoarthritis (OA) is a progressively degenerative joint disorder characterized by degradation of extracellular matrix (ECM) molecules, loss of articular cartilages, and formation of osteophytes. In OA, dysfunction of articular chondrocytes compromises synthesis of ECM and enhances degradation of ECM, which leads to loss of ECM and cartilage degradation. Aggrecan (ACAN) is the most prominent proteoglycan in cartilage, which holds a large amount of water and ions, and confers mechanical elasticity. ECM including ACAN and collagens are degraded by matrix metalloproteinases (MMPs), aggrecanases (ADAMTSs), and other matrix proteases [2,3]. Chondrocytes orchestrate fine-tuned gene expressions of ECM molecules and their catabolic enzymes to achieve tolerance to mechanical stress as well as elasticity of articular cartilages, which is compromised in OA
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