Abstract
Transient receptor potential vanilloid 4 (TRPV4) plays an important role in chondrocytes via Ca2+ signaling. However, its role in the progression of osteoarthritis is unclear. This study aimed to evaluate the effects of TRPV4 activation on articular cartilage and chondrocytes stimulated with interleukin (IL)-1β. Bovine and human articular chondrocytes were stimulated with various agents, including IL-1β, GSK1016790A (GSK101; a TRPV4 agonist), Compound C (an AMP-activated protein kinase (AMPK) inhibitor), and STO-609 (a calmodulin-dependent protein kinase kinase (CaMKK) inhibitor), and were processed for Western blot analysis and real-time PCR. The dimethylmethylene blue (DMMB) assay and Safranin O staining were also performed. GSK101 reversed the IL-1β-induced increase in expression of matrix metalloproteinase (MMP)-13 and decrease in expression of aggrecan. GSK101 also decreased proteoglycan release in the DMMB assay and retained Safranin O staining of articular cartilage tissue. Furthermore, GSK101 increased AMPK phosphorylation and decreased IL-1β-induced nuclear factor kappa B (NF-κB) phosphorylation. Compound C and STO-609 reversed the suppressive effects of GSK101 on NF-κB activation and MMP-13 expression. In conclusion, TRPV4 activation had chondroprotective effects on articular cartilage stimulated with IL-1β by activating CaMKK/AMPK and suppressing the NF-κB pathway. TRPV4 activators may offer a promising therapeutic option for preventing the progression of osteoarthritis.
Highlights
Transient receptor potential vanilloid 4 (TRPV4), an osmotically active ion channel associated with Ca2+ intake, plays an important role in mechano-transduction pathways of chondrocytes via Ca2+ signaling[1,2,3]
We previously reported that TRPV4 stimulated with GSK101 plays a role in chondrogenesis by inducing the expression of chondrogenic markers including sex-determining region Y-box transcription factor (SOX9) and aggrecan (AGC)[8], whereas signaling pathways of up-regulation of SOX9 and AGC via activation of TRPV4 was not well shown
In bovine articular chondrocytes (BACs), GSK101 significantly reversed the IL-1β-induced increase in expression of matrix metalloproteinase (MMP-)[13] mRNA and decrease in expression of AGC and SOX9 mRNA in a dose-dependent manner (Fig. 1b)
Summary
Transient receptor potential vanilloid 4 (TRPV4), an osmotically active ion channel associated with Ca2+ intake, plays an important role in mechano-transduction pathways of chondrocytes via Ca2+ signaling[1,2,3]. Previous studies have shown that TRPV4 activation induced both catabolic and anabolic responses in chondrocytes in vitro[3,4,5]. We previously reported that TRPV4 stimulated with GSK101 plays a role in chondrogenesis by inducing the expression of chondrogenic markers including sex-determining region Y-box transcription factor (SOX9) and aggrecan (AGC)[8], whereas signaling pathways of up-regulation of SOX9 and AGC via activation of TRPV4 was not well shown. Inflammation, which plays a role in modern chronic diseases such as diabetes and c ancer[15], the role of this pathway in articular cartilage degradation and OA progression is unknown. The present study aimed to determine whether TRPV4 activation in chondrocytes protects articular cartilage from degradation and inhibits the progression of OA via the CaMKK/AMPK/NF-κB signaling pathway
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