Intervertebral disc degeneration(IDD)is a major cause of discogenic pain,and is attributed to the dysfunction of nucleus pulposus,annulus fibrosus,and cartilaginous endplate(CEP).Osteopontin(OPN),a glycoprotein,is hig...Intervertebral disc degeneration(IDD)is a major cause of discogenic pain,and is attributed to the dysfunction of nucleus pulposus,annulus fibrosus,and cartilaginous endplate(CEP).Osteopontin(OPN),a glycoprotein,is highly expressed in the CEP.However,little is known on how OPN regulates CEP homeostasis and degeneration,contributing to the pathogenesis of IDD.Here,we investigate the roles of OPN in CEP degeneration in a mouse IDD model induced by lumbar spine instability and its impact on the degeneration of endplate chondrocytes(EPCs)under pathological conditions.OPN is mainly expressed in the CEP and decreases with degeneration in mice and human patients with severe IDD.Conditional Spp1 knockout in EPCs of adult mice enhances age-related CEP degeneration and accelerates CEP remodeling during IDD.Mechanistically,OPN deficiency increases CCL2 and CCL5 production in EPCs to recruit macrophages and enhances the activation of NLRP3 inflammasome and NF-κB signaling by facilitating assembly of IRAK1-TRAF6 complex,deteriorating CEP degeneration in a spatiotemporal pattern.More importantly,pharmacological inhibition of the NF-κB/NLRP3 axis attenuates CEP degeneration in OPN-deficient IDD mice.Overall,this study highlights the importance of OPN in maintaining CEP and disc homeostasis,and proposes a promising therapeutic strategy for IDD by targeting the NF-κB/NLRP3 axis.展开更多
Low back pain,mainly caused by intervertebral disc degeneration(IVDD),is a common health problem;however,current surgical treatments are less than satisfactory.Thus,it is essential to develop novel non-invasive surgic...Low back pain,mainly caused by intervertebral disc degeneration(IVDD),is a common health problem;however,current surgical treatments are less than satisfactory.Thus,it is essential to develop novel non-invasive surgical methods for IVDD treatment.Here,we describe a therapeutic strategy to inhibit IVDD by injecting hydrogels modified with the extracellular matrix of costal cartilage(ECM-Gels)that are loaded with cartilage endplate stem cells(CESCs).After loaded with CESCs overexpressing Sphk2(Lenti-Sphk2-CESCs)and injected near the cartilage endplate(CEP)of rats in vivo,ECM-Gels produced Sphk2-engineered exosomes(Lenti-Sphk2-Exos).These exosomes penetrated the annulus fibrosus(AF)and transported Sphk2 into the nucleus pulposus cells(NPCs).Sphk2 activated the phosphatidylinositol 3-kinase(PI3K)/p-AKT pathway as well as the intracellular autophagy of NPCs,ultimately ameliorating IVDD.This study provides a novel and efficient non-invasive combinational strategy for IVDD treatment using injectable ECM-Gels loaded with CESCs that express Sphk2 with sustained release of functional exosomes.展开更多
基金supported by Chongqing Municipal Natural Science Foundation (CSTB2022NSCQ-MSX1366)National Natural Science Foundation of China (81702182,81874087)+1 种基金Chongqing Outstanding Young Talent Supporting Program (cstc2024ycjhbgzxm0031)the Special Project for Talent Development of Xinqiao Hospital (2022XKRC006)。
文摘Intervertebral disc degeneration(IDD)is a major cause of discogenic pain,and is attributed to the dysfunction of nucleus pulposus,annulus fibrosus,and cartilaginous endplate(CEP).Osteopontin(OPN),a glycoprotein,is highly expressed in the CEP.However,little is known on how OPN regulates CEP homeostasis and degeneration,contributing to the pathogenesis of IDD.Here,we investigate the roles of OPN in CEP degeneration in a mouse IDD model induced by lumbar spine instability and its impact on the degeneration of endplate chondrocytes(EPCs)under pathological conditions.OPN is mainly expressed in the CEP and decreases with degeneration in mice and human patients with severe IDD.Conditional Spp1 knockout in EPCs of adult mice enhances age-related CEP degeneration and accelerates CEP remodeling during IDD.Mechanistically,OPN deficiency increases CCL2 and CCL5 production in EPCs to recruit macrophages and enhances the activation of NLRP3 inflammasome and NF-κB signaling by facilitating assembly of IRAK1-TRAF6 complex,deteriorating CEP degeneration in a spatiotemporal pattern.More importantly,pharmacological inhibition of the NF-κB/NLRP3 axis attenuates CEP degeneration in OPN-deficient IDD mice.Overall,this study highlights the importance of OPN in maintaining CEP and disc homeostasis,and proposes a promising therapeutic strategy for IDD by targeting the NF-κB/NLRP3 axis.
基金supported by the National Natural Science Foundation of China(Grant Number:81874028,81702182)the Research Program of Foundation Science and Application Technology of Chongqing(Grant Number:cstc2018jcyjAX0598)Basic Medical College Foundation of Army Medical University(2019JCZX10).
文摘Low back pain,mainly caused by intervertebral disc degeneration(IVDD),is a common health problem;however,current surgical treatments are less than satisfactory.Thus,it is essential to develop novel non-invasive surgical methods for IVDD treatment.Here,we describe a therapeutic strategy to inhibit IVDD by injecting hydrogels modified with the extracellular matrix of costal cartilage(ECM-Gels)that are loaded with cartilage endplate stem cells(CESCs).After loaded with CESCs overexpressing Sphk2(Lenti-Sphk2-CESCs)and injected near the cartilage endplate(CEP)of rats in vivo,ECM-Gels produced Sphk2-engineered exosomes(Lenti-Sphk2-Exos).These exosomes penetrated the annulus fibrosus(AF)and transported Sphk2 into the nucleus pulposus cells(NPCs).Sphk2 activated the phosphatidylinositol 3-kinase(PI3K)/p-AKT pathway as well as the intracellular autophagy of NPCs,ultimately ameliorating IVDD.This study provides a novel and efficient non-invasive combinational strategy for IVDD treatment using injectable ECM-Gels loaded with CESCs that express Sphk2 with sustained release of functional exosomes.
