Osteoarthritis(OA),the most prevalent degenerative joint disease,is marked by cartilage degradation and pathological alterations in surrounding tissues.Currently,no effective disease-modifying treatments exist.This st...Osteoarthritis(OA),the most prevalent degenerative joint disease,is marked by cartilage degradation and pathological alterations in surrounding tissues.Currently,no effective disease-modifying treatments exist.This study aimed to elucidate the critical roles of Myb-like,SWIRM,and MPN domains 1(MYSM1)and its downstream effector,Receptor-interacting protein kinase 2(RIPK2),in OA pathogenesis and the underlying mechanisms.Our findings revealed reduced MYSM1 levels in the cartilage of OA patients and mouse models.Genetic or adenovirus-induced MYSM1 knockout exacerbated OA progression in mice,whereas MYSM1 overexpression mitigated it.Mechanistically,MYSM1 inhibited the NF-κB and MAPK signaling pathways.Conversely,downstream RIPK2 significantly increased OA-like phenotypes and activated the NF-κB and MAPK pathways.The Ripk2^(S176D) mutation accelerated OA pathogenesis,while Ripk2 silencing or Ripk2^(S176A)mutation deactivated NF-κB and MAPK pathways,counteracting the role of MYSM1.MYSM1 deubiquitinates and dephosphorylates RIPK2^(S176)by recruiting protein phosphatase 2 A(PP2A).These results suggest that targeting MYSM1 or downstream RIPK2 offers promising therapeutic potential for OA.展开更多
蛋白磷酸酶2A(PP2A)是由36 k Da的催化亚基C(PP2Ac)和65 k Da的结构亚基A(PP2Aα/β)一起组成PP2A的核心酶,并且和各种不同的调节亚基B形成具有不同功能的PP2A全酶复合体。在细胞中PP2A发挥着重要作用,特别是在抑制肿瘤的形成当中,编码P...蛋白磷酸酶2A(PP2A)是由36 k Da的催化亚基C(PP2Ac)和65 k Da的结构亚基A(PP2Aα/β)一起组成PP2A的核心酶,并且和各种不同的调节亚基B形成具有不同功能的PP2A全酶复合体。在细胞中PP2A发挥着重要作用,特别是在抑制肿瘤的形成当中,编码PP2Aα/β基因的突变将导致肿瘤的形成和其他疾病。当非小细胞肺癌细胞H1299中过表达PP2A-Aα时,细胞生长被抑制,细胞周期停留在G0/G1期,致瘤能力也同时被抑制。进一步研究证明当PP2A-Aα过表达时,Akt被去磷酸化失活使Skp2的表达下调,从而导致细胞周期抑制因子p27kip1的表达上调。肿瘤细胞软琼脂克隆形成实验的结果表明过表达PP2A-Aα之后H1299细胞的锚定非依赖性生长能力明显的降低,形成的克隆细胞团也较小,这些结果和裸鼠成瘤实验的结果是一致的。展开更多
基金National Natural Science Foundation of China(Nos.82330075 and 81401047)Postdoctoral Fellowship Program of China Postdoctoral Science Foundation(GZC20241275)。
文摘Osteoarthritis(OA),the most prevalent degenerative joint disease,is marked by cartilage degradation and pathological alterations in surrounding tissues.Currently,no effective disease-modifying treatments exist.This study aimed to elucidate the critical roles of Myb-like,SWIRM,and MPN domains 1(MYSM1)and its downstream effector,Receptor-interacting protein kinase 2(RIPK2),in OA pathogenesis and the underlying mechanisms.Our findings revealed reduced MYSM1 levels in the cartilage of OA patients and mouse models.Genetic or adenovirus-induced MYSM1 knockout exacerbated OA progression in mice,whereas MYSM1 overexpression mitigated it.Mechanistically,MYSM1 inhibited the NF-κB and MAPK signaling pathways.Conversely,downstream RIPK2 significantly increased OA-like phenotypes and activated the NF-κB and MAPK pathways.The Ripk2^(S176D) mutation accelerated OA pathogenesis,while Ripk2 silencing or Ripk2^(S176A)mutation deactivated NF-κB and MAPK pathways,counteracting the role of MYSM1.MYSM1 deubiquitinates and dephosphorylates RIPK2^(S176)by recruiting protein phosphatase 2 A(PP2A).These results suggest that targeting MYSM1 or downstream RIPK2 offers promising therapeutic potential for OA.
文摘蛋白磷酸酶2A(PP2A)是由36 k Da的催化亚基C(PP2Ac)和65 k Da的结构亚基A(PP2Aα/β)一起组成PP2A的核心酶,并且和各种不同的调节亚基B形成具有不同功能的PP2A全酶复合体。在细胞中PP2A发挥着重要作用,特别是在抑制肿瘤的形成当中,编码PP2Aα/β基因的突变将导致肿瘤的形成和其他疾病。当非小细胞肺癌细胞H1299中过表达PP2A-Aα时,细胞生长被抑制,细胞周期停留在G0/G1期,致瘤能力也同时被抑制。进一步研究证明当PP2A-Aα过表达时,Akt被去磷酸化失活使Skp2的表达下调,从而导致细胞周期抑制因子p27kip1的表达上调。肿瘤细胞软琼脂克隆形成实验的结果表明过表达PP2A-Aα之后H1299细胞的锚定非依赖性生长能力明显的降低,形成的克隆细胞团也较小,这些结果和裸鼠成瘤实验的结果是一致的。
