title: Verapamil protects against cartilage degradation in osteoarthritis by inhibiting Wnt/β-catenin signaling.
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.
authors.affiliation: Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan; Department of Orthopaedic Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Takamatsu
authors.affiliation: Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Bisei
authors.initials: B
authors.lastname: Ohkawara
authors.affiliation: Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Mikako
authors.initials: M
authors.lastname: Ito
authors.affiliation: Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Akio
authors.initials: A
authors.lastname: Masuda
authors.affiliation: Department of Orthopaedic Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Tadahiro
authors.initials: T
authors.lastname: Sakai
authors.affiliation: Department of Orthopaedic Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Ishiguro
authors.affiliation: Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Kinji
authors.initials: K
authors.lastname: Ohno
mesh_terms: D000818:Animals; D015415:Biomarkers; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002356:Cartilage / Q000187:drug effects* / Q000473:pathology*; D019902:Chondrocytes / Q000187:drug effects / Q000378:metabolism; D020219:Chondrogenesis / Q000187:drug effects / Q000235:genetics; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D006023:Glycoproteins / Q000235:genetics; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D010003:Osteoarthritis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D011401:Promoter Regions, Genetic; D011509:Proteoglycans / Q000378:metabolism; D051381:Rats; D014700:Verapamil / Q000494:pharmacology*; D051153:Wnt Proteins / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D051176:beta Catenin / Q000378:metabolism; D000099274:Frizzled-Related Proteins
chemical_list: D015415:Biomarkers; D002121:Calcium Channel Blockers; D006023:Glycoproteins; D047908:Intracellular Signaling Peptides and Proteins; D011509:Proteoglycans; D014700:Verapamil; D051153:Wnt Proteins; D051176:beta Catenin; D000099274:Frizzled-Related Proteins