| 1 | IRE1α regulates the PTHrP-IHH feedback loop to orchestrate chondrocyte hypertrophy and cartilage mineralization显示文摘Cartilage development is controlled by the highly synergistic proliferation and differentiation of growth plate chondrocytes,in which the Indian hedgehog(IHH)and parathyroid hormone-related protein-parathyroid hormone-1 receptor(PTHrP-PTH1R)feedback loop is crucial.The inositol-requiring enzyme 1a/X-box-binding protein-1 spliced(IRE1α/XBP1s)branch of the unfolded protein response(UPR)is essential for normal cartilage development.However,the precise role of ER stress effector IRE1α,encoded by endoplasmic reticulum to nucleus signaling 1(ERN1),in skeletal development remains unknown.Herein,we reported that loss of IRE1α accelerates chondrocyte hypertrophy and promotes endochondral bone growth.ERN1 acts as a negative regulator of chondrocyte proliferation and differentiation in postnatal growth plates.Its deficiency interrupted PTHrP/PTH1R and IHH homeostasis leading to impaired chondrocyte hypertrophy and differentiation.XBP1s,produced by p-IRE1α-mediated splicing,binds and up-regulates PTH1R and IHH,which coordinate cartilage development.Meanwhile,ER stress cannot be activated normally in ERN1-deficient chondrocytes.In conclusion,ERN1 deficiency accelerates chondrocyte hypertrophy and cartilage mineralization by impairing the homeostasis of the IHH and PTHrP/PTH1R feedback loop and ER stress.ERN1 may have a potential role as a new target for cartilage growth and maturation. | Mengtian Fan Nana Geng Xingyue Li Danyang Yin Yuyou Yang Rong Jiang Cheng Chen Naibo Feng Li Liang Xiaoli Li Fengtao Luo Huabing Qi Qiaoyan Tan Yangli Xie Fengjin Guo | 2024 | Genes & Diseases2024，11，1： | 0 |
| 2 | Progranulin regulation of autophagy contributes to its chondroprotective effect in osteoarthritis显示文摘Progranulin(PGRN)is a multifunctional growth factor involved in many physiolog-ical processes and disease states.The apparent protective role of PGRN and the importance of chondrocyte autophagic function in the progression of osteoarthritis(OA)led us to investi-gate the role of PGRN in the regulation of chondrocyte autophagy.PGRN knockout chondro-cytes exhibited a deficient autophagic response with limited induction following rapamycin,serum starvation,and IL-1b-induced autophagy.PGRN-mediated anabolism and suppression of IL-1b-induced catabolism were largely abrogated in the presence of the BafA1 autophagy inhibitor.Mechanistically,during the process of OA,PGRN and the ATG5eATG12 conjugate form a protein complex;PGRN regulates autophagy in chondrocytes and OA through,at least partially,the interactions between PGRN and the ATG5eATG12 conjugate.Furthermore,the ATG5eATG12 conjugate is critical for cell proliferation and apoptosis.Knockdown or knockout of ATG5 reduces the expression of ATG5eATG12 conjugate and inhibits the chondroprotective effect of PGRN on anabolism and catabolism.Overexpression of PGRN partially reversed this effect.In brief,the PGRN-mediated regulation of chondrocyte autophagy plays a key role in the chondroprotective role of PGRN in OA.Such studies provide new insights into the pathogen-esis of OA and PGRN-associated autophagy in chondrocyte homeostasis. | Yiming Pan Yuyou Yang Mengtian Fan Cheng Chen Rong Jiang Li Liang Menglin Xian Biao Kuang Nana Geng Naibo Feng Lin Deng Wei Zheng Fengmei Zhang Xiaoli Li Fengjin Guo | 2023 | Genes & Diseases2023，10，4： | 0 |
您所在的机构暂未开通此部分的功能，请联系管理员