Osteoarthritis(OA)is one of the most common chronic diseases in the world.However,current treatment modalities mainly relieve pain and inhibit cartilage degradation,but do not promote cartilage regeneration.In this st...Osteoarthritis(OA)is one of the most common chronic diseases in the world.However,current treatment modalities mainly relieve pain and inhibit cartilage degradation,but do not promote cartilage regeneration.In this study,we show that G protein-coupled receptor class C group 5 member B(GPRC5B),an orphan G-protein-couple receptor,not only inhibits cartilage degradation,but also increases cartilage regeneration and thereby is protective against OA.We observed that Gprc5b deficient chondrocytes had an upregulation of cartilage catabolic gene expression,along with downregulation of anabolic genes in vitro.Furthermore,mice deficient in Gprc5b displayed a more severe OA phenotype in the destabilization of the medial meniscus(DMM)induced OA mouse model,with upregulation of cartilage catabolic factors and downregulation of anabolic factors,consistent with our in vitro findings.Overexpression of Gprc5b by lentiviral vectors alleviated the cartilage degeneration in DMM-induced OA mouse model by inhibiting cartilage degradation and promoting regeneration.We also assessed the molecular mechanisms downstream of Gprc5b that may mediate these observed effects and identify the role of protein kinase B(AKT)-mammalian target of rapamycin(m TOR)-autophagy signaling pathway.Thus,we demonstrate an integral role of GPRC5B in OA pathogenesis,and activation of GPRC5B has the potential in preventing the progression of OA.展开更多
基金supported by grants from the National Key Research and Development Program of China(2020YFC2002800 and 2018YFC1105102 to Jian Luo)the National Natural Science Foundation of China(82225030,92168204 and 9194910271 to Jian Luo)+2 种基金Shanghai Municipal Health Commission Excellent Young Medical Talents Training Program(2022XD034 to Jian Luo,China)the Fundamental Research Funds for the Central Universities(22120210586 to Jian Luo,China)the East China Normal University(ECNU)Multifunctional Platform for Innovation(011)。
文摘Osteoarthritis(OA)is one of the most common chronic diseases in the world.However,current treatment modalities mainly relieve pain and inhibit cartilage degradation,but do not promote cartilage regeneration.In this study,we show that G protein-coupled receptor class C group 5 member B(GPRC5B),an orphan G-protein-couple receptor,not only inhibits cartilage degradation,but also increases cartilage regeneration and thereby is protective against OA.We observed that Gprc5b deficient chondrocytes had an upregulation of cartilage catabolic gene expression,along with downregulation of anabolic genes in vitro.Furthermore,mice deficient in Gprc5b displayed a more severe OA phenotype in the destabilization of the medial meniscus(DMM)induced OA mouse model,with upregulation of cartilage catabolic factors and downregulation of anabolic factors,consistent with our in vitro findings.Overexpression of Gprc5b by lentiviral vectors alleviated the cartilage degeneration in DMM-induced OA mouse model by inhibiting cartilage degradation and promoting regeneration.We also assessed the molecular mechanisms downstream of Gprc5b that may mediate these observed effects and identify the role of protein kinase B(AKT)-mammalian target of rapamycin(m TOR)-autophagy signaling pathway.Thus,we demonstrate an integral role of GPRC5B in OA pathogenesis,and activation of GPRC5B has the potential in preventing the progression of OA.
