Although aging has traditionally been viewed as the most important risk factor for osteoarthritis(OA),an increasing amount of epidemiological evidence has highlighted the association between metabolic abnormalities an...Although aging has traditionally been viewed as the most important risk factor for osteoarthritis(OA),an increasing amount of epidemiological evidence has highlighted the association between metabolic abnormalities and OA,particularly in younger individuals.Metabolic abnormalities,such as obesity and typeⅡdiabetes,are strongly linked to OA,and they affect both weightbearing and non-weight-bearing joints,thus suggesting that the pathogenesis of OA is more complicated than the mechanical stress induced by overweight.This review aims to explore the recent advances in research on the relationship between metabolic abnormalities and OA risk,including the impact of abnormal glucose and lipid metabolism,the potential pathogenesis and targeted therapeutic strategies.展开更多
Spine degeneration is an aging-related disease,but its molecular mechanisms remain unknown,although elevatedβ-catenin signaling has been reported to be involved in intervertebral disc degeneration.Here,we determined ...Spine degeneration is an aging-related disease,but its molecular mechanisms remain unknown,although elevatedβ-catenin signaling has been reported to be involved in intervertebral disc degeneration.Here,we determined the role ofβ-catenin signaling in spinal degeneration and in the homeostasis of the functional spinal unit(FSU),which includes the intervertebral disc,vertebra and facet joint and is the smallest physiological motion unit of the spine.We showed that pain sensitivity in patients with spinal degeneration is highly correlated withβ-catenin protein levels.We then generated a mouse model of spinal degeneration by transgenic expression of constitutively activeβ-catenin in Col2^(+) cells.We found thatβ-catenin-TCF7 activated the transcription of CCL2,a known critical factor in osteoarthritic pain.Using a lumbar spine instability model,we showed that aβ-catenin inhibitor relieved low back pain.Our study indicates thatβ-catenin plays a critical role in maintaining spine tissue homeostasis,its abnormal upregulation leads to severe spinal degeneration,and its targeting could be an avenue to treat this condition.展开更多
Despite the diverse roles of tripartite motif(Trim)-containing proteins in the regulation of autophagy,the innate immune response,and cell differentiation,their roles in skeletal diseases are largely unknown.We recent...Despite the diverse roles of tripartite motif(Trim)-containing proteins in the regulation of autophagy,the innate immune response,and cell differentiation,their roles in skeletal diseases are largely unknown.We recently demonstrated that Trim21 plays a crucial role in regulating osteoblast(OB)differentiation in osteosarcoma.However,how Trim21 contributes to skeletal degenerative disorders,including osteoporosis,remains unknown.First,human and mouse bone specimens were evaluated,and the results showed that Trim21 expression was significantly elevated in bone tissues obtained from osteoporosis patients.Next,we found that global knockout of the Trim21 gene(KO,Trim2^(1-/-))resulted in higher bone mass compared to that of the control littermates.We further demonstrated that loss of Trim21 promoted bone formation by enhancing the osteogenic differentiation of bone marrow mesenchymal stem cells(BMSCs)and elevating the activity of OBs;moreover,Trim21 depletion suppressed osteoclast(OC)formation of RAW264.7 cells.In addition,the differentiation of OCs from bone marrow-derived macrophages(BMMs)isolated from Trim21^(-/-)and Ctsk-cre;Trim21^(f/f)mice was largely compromised compared to that of the littermate control mice.Mechanistically,YAP1/β-catenin signaling was identified and demonstrated to be required for the Trim21-mediated osteogenic differentiation of BMSCs.More importantly,the loss of Trim21 prevented ovariectomy(OVX)-and lipopolysaccharide(LPS)-induced bone loss in vivo by orchestrating the coupling of OBs and OCs through YAP1 signaling.Our current study demonstrated that Trim21 is crucial for regulating OB-mediated bone formation and OC-mediated bone resorption,thereby providing a basis for exploring Trim21 as a novel dual-targeting approach for treating osteoporosis and pathological bone loss.展开更多
Osteoarthritis(OA)is the most common degenerative joint disease that causes painful swelling and permanent damage to the joints in the body.The molecular mechanisms of OA are currently unknown.OA is a heterogeneous di...Osteoarthritis(OA)is the most common degenerative joint disease that causes painful swelling and permanent damage to the joints in the body.The molecular mechanisms of OA are currently unknown.OA is a heterogeneous disease that affects the entire joint,and multiple tissues are altered during OA development.To better understand the pathological mechanisms of OA,new approaches,methods,and techniques need to be used to understand OA pathogenesis.In this review,we first focus on the epigenetic regulation of OA,with a particular focus on DNA methylation,histone modification,and microRNA regulation,followed by a summary of several key mediators in OA-associated pain.We then introduce several innovative techniques that have been and will continue to be used in the fields of OA and OA-associated pain,such as CRISPR,scRNA sequencing,and lineage tracing.Next,we discuss the timely updates concerning cell death regulation in OA pathology,including pyroptosis,ferroptosis,and autophagy,as well as their individual roles in OA and potential molecular targets in treating OA.Finally,our review highlights new directions on the role of the synovial lymphatic system in OA.An improved understanding of OA pathogenesis will aid in the development of more specific and effective therapeutic interventions for OA.展开更多
Osteoarthritis(OA)is a degenerative disease involving entire joint.It is often initiated from the low-grade inflammation in synovial tissue and then affects articular cartilage and subchondral bone.Multiple risk facto...Osteoarthritis(OA)is a degenerative disease involving entire joint.It is often initiated from the low-grade inflammation in synovial tissue and then affects articular cartilage and subchondral bone.Multiple risk factors,such as aging,mechanical overloading,trauma,overuse,etc.are involved in OA development.Several approaches have been utilized to repair cartilage defects.Among them,biomaterials-based mes-enchymal stromal cell(MSCs)therapy is considered as the most promising modality.The burgeoning material science and manufacturing technologies,such as 3D printing,allow us to mimic native articu-lar cartilage and regulate the artificial cartilage development,regeneration and functional restoration.In this review article,we will summarize the recent progress of biomaterials combined with MSCs or chon-drocytes in repairing cartilage damage induced by OA.Several typical natural and synthetic biomaterials,such as collagen,alginate,hyaluronic acid and poly(ethylene glycol),polylactide acid,polyurethane,etc.for cartilage repairing will be introduced.Moreover,critical signaling pathways associated with the pro-gression of OA,as well as the targeted pharmacologic,genetic therapies and tissue engineering scaffolds for OA and cartilage repairing are presented.We will also provide our prospects for future directions in this active research area.展开更多
Plastic and elastic behaviors of organic crystals have profound influence on the processability of pharmaceutical substances.Analogous to metals,the identifications of molecular slip planes in organic crystals are reg...Plastic and elastic behaviors of organic crystals have profound influence on the processability of pharmaceutical substances.Analogous to metals,the identifications of molecular slip planes in organic crystals are regarded as a strategy for harnessing plasticity.In this work,we experimentally characterized the form II anhydrous theophylline(THPa)and its monohydrate(THPm)for their distinct plastic and elastic behaviors.Extensive DFT calculations were performed to model the effects of increasing lattice strains on molecular packing.We discovered that the energy barrier associated with the strain-induced molecular rearrangement would link to the plasticity of THPa,and possibly other simple aromatic compounds.Meanwhile,water molecules in THPm disrupt the stacking architecture from THPm and effectively undermine the general mechanism for plasticity.Hydrate formation would therefore be an alternative strategy to engineer the mechanical property of organic crystalline materials.展开更多
Osteoarthritis(OA)is a painful degenerative joint disease and is the leading cause of chronic disability among elderly individuals.To improve the quality of life for patients with OA,the primary goal for OA treatment ...Osteoarthritis(OA)is a painful degenerative joint disease and is the leading cause of chronic disability among elderly individuals.To improve the quality of life for patients with OA,the primary goal for OA treatment is to relieve the pain.During OA progression,nerve ingrowth was observed in synovial tissue and articular cartilage.These abnormal neonatal nerves act as nociceptors to detect OA pain signals.The molecular mechanisms for transmitting OA pain in the joint tissues to the central nerve system(CNS)is currently unknown.MicroRNA miR-204 has been demonstrated to maintain the homeostasis of joint tissues and have chondro-protective effect on OA pathogenesis.However,the role of miR-204 in OA pain has not been determined.In this study,we investigated interactions between chondrocytes and neural cells and evaluated the effect and mechanism of miR-204 delivered by exosome in the treatment of OA pain in an experimental OA mouse model.Our findings demonstrated that miR-204 could protect OA pain by inhibition of SP1-LDL Receptor Related Protein 1(LRP1)signaling and blocking neuro-cartilage interaction in the joint.Our studies defined novel molecular targets for the treatment of OA pain.展开更多
基金supported by the National Key Research and Development Program of China(2021YFB3800800)to L.T.and D.Csupported by the National Natural Science Foundation of China(NSFC)grants(82030067,82161160342 and 82250710174)to D.C.,grant 82360429 to Y.C and grant 82172397 to L.T+5 种基金supported by National Science Foundation of Guangxi(2022JJA141126)Advanced Innovation Teams and Xinghu Scholars Program of Guangxi Medical UniversityChina Postdoctoral Science Foundation(2019M650235)Key R&D Project of Qingxiu District,Nanning,Guangxi(2021003)to Y.C.the Hong Kong RGC grant HKU-17101821 to W.W.L.and D.C.SIAT Innovation Program for Excellent Young Researchers to K.L.
文摘Although aging has traditionally been viewed as the most important risk factor for osteoarthritis(OA),an increasing amount of epidemiological evidence has highlighted the association between metabolic abnormalities and OA,particularly in younger individuals.Metabolic abnormalities,such as obesity and typeⅡdiabetes,are strongly linked to OA,and they affect both weightbearing and non-weight-bearing joints,thus suggesting that the pathogenesis of OA is more complicated than the mechanical stress induced by overweight.This review aims to explore the recent advances in research on the relationship between metabolic abnormalities and OA risk,including the impact of abnormal glucose and lipid metabolism,the potential pathogenesis and targeted therapeutic strategies.
基金supported by the National Key Research and Development Program of China(2021YFB3800800)to L.T.and D.C.supported by the National Natural Science Foundation of China(NSFC)grants 82030067,82161160342,and 82250710174 to D.C.+1 种基金NSFC grant 82172397 to L.T.supported by the Chinese Postdoctoral Science Foundation(2022M710158)。
文摘Spine degeneration is an aging-related disease,but its molecular mechanisms remain unknown,although elevatedβ-catenin signaling has been reported to be involved in intervertebral disc degeneration.Here,we determined the role ofβ-catenin signaling in spinal degeneration and in the homeostasis of the functional spinal unit(FSU),which includes the intervertebral disc,vertebra and facet joint and is the smallest physiological motion unit of the spine.We showed that pain sensitivity in patients with spinal degeneration is highly correlated withβ-catenin protein levels.We then generated a mouse model of spinal degeneration by transgenic expression of constitutively activeβ-catenin in Col2^(+) cells.We found thatβ-catenin-TCF7 activated the transcription of CCL2,a known critical factor in osteoarthritic pain.Using a lumbar spine instability model,we showed that aβ-catenin inhibitor relieved low back pain.Our study indicates thatβ-catenin plays a critical role in maintaining spine tissue homeostasis,its abnormal upregulation leads to severe spinal degeneration,and its targeting could be an avenue to treat this condition.
基金supported by the Natural Science Foundation with grants from the National Key R&D Program of China(2018YFC2002500)National Natural Science Foundation of China(81602360,82072470,82350003,92049201)+6 种基金Key Laboratory Construction Project of Guangzhou Science and Technology Bureau(202102100007)supported by the Clinical Frontier Technology Program of the First Affiliated Hospital of Jinan University,China(No.JNU1AF-CFTP-2022-a01221)Natural Science Foundation of Guangdong Province(2021A1515012154,2019A1515011082,2017A030313665,2018A030313544,2020B1515120038)Science and Technology Projects in Guangzhou(201707010493,202102010069)Macao Foundation for Development of Science and Technology(0029/2019/A)Youth Talent Support Project of Guangzhou Association for Science&Technology(X20200301018)pilot project of clinical collaboration from National Administration of Traditional Chinese Medicine and National Health Commission of the People’s Republic of China and Logistics Support Department of the Central Military Commission。
文摘Despite the diverse roles of tripartite motif(Trim)-containing proteins in the regulation of autophagy,the innate immune response,and cell differentiation,their roles in skeletal diseases are largely unknown.We recently demonstrated that Trim21 plays a crucial role in regulating osteoblast(OB)differentiation in osteosarcoma.However,how Trim21 contributes to skeletal degenerative disorders,including osteoporosis,remains unknown.First,human and mouse bone specimens were evaluated,and the results showed that Trim21 expression was significantly elevated in bone tissues obtained from osteoporosis patients.Next,we found that global knockout of the Trim21 gene(KO,Trim2^(1-/-))resulted in higher bone mass compared to that of the control littermates.We further demonstrated that loss of Trim21 promoted bone formation by enhancing the osteogenic differentiation of bone marrow mesenchymal stem cells(BMSCs)and elevating the activity of OBs;moreover,Trim21 depletion suppressed osteoclast(OC)formation of RAW264.7 cells.In addition,the differentiation of OCs from bone marrow-derived macrophages(BMMs)isolated from Trim21^(-/-)and Ctsk-cre;Trim21^(f/f)mice was largely compromised compared to that of the littermate control mice.Mechanistically,YAP1/β-catenin signaling was identified and demonstrated to be required for the Trim21-mediated osteogenic differentiation of BMSCs.More importantly,the loss of Trim21 prevented ovariectomy(OVX)-and lipopolysaccharide(LPS)-induced bone loss in vivo by orchestrating the coupling of OBs and OCs through YAP1 signaling.Our current study demonstrated that Trim21 is crucial for regulating OB-mediated bone formation and OC-mediated bone resorption,thereby providing a basis for exploring Trim21 as a novel dual-targeting approach for treating osteoporosis and pathological bone loss.
基金supported by the National Natural Science Foundation of China(NSFC)grants(82030067,82161160342,and 82172397)to D.C.and L.T.a grant from the Youth Innovation Promotion Association of the Chinese Academy of Sciences(2020353)to L.T.+1 种基金supported by the National Key Research and Development Program of China(2021YFB3800800 to L.T.and D.C)supported by the research grant NIH AG0599775.
文摘Osteoarthritis(OA)is the most common degenerative joint disease that causes painful swelling and permanent damage to the joints in the body.The molecular mechanisms of OA are currently unknown.OA is a heterogeneous disease that affects the entire joint,and multiple tissues are altered during OA development.To better understand the pathological mechanisms of OA,new approaches,methods,and techniques need to be used to understand OA pathogenesis.In this review,we first focus on the epigenetic regulation of OA,with a particular focus on DNA methylation,histone modification,and microRNA regulation,followed by a summary of several key mediators in OA-associated pain.We then introduce several innovative techniques that have been and will continue to be used in the fields of OA and OA-associated pain,such as CRISPR,scRNA sequencing,and lineage tracing.Next,we discuss the timely updates concerning cell death regulation in OA pathology,including pyroptosis,ferroptosis,and autophagy,as well as their individual roles in OA and potential molecular targets in treating OA.Finally,our review highlights new directions on the role of the synovial lymphatic system in OA.An improved understanding of OA pathogenesis will aid in the development of more specific and effective therapeutic interventions for OA.
基金financially supported by the National Key Re-search and Development Program of China(No.2021YFB3800800)the National Natural Science Foundation of China(NSFC)(Nos.82030067,82161160342,82172397,82250710174 and 31922040)+1 种基金the Youth Innovation Promotion Association of Chinese Academy of Sciences(No.2020353)the Shenzhen Science and Technol-ogy Research Funding(No.JCYJ20220818101414032).
文摘Osteoarthritis(OA)is a degenerative disease involving entire joint.It is often initiated from the low-grade inflammation in synovial tissue and then affects articular cartilage and subchondral bone.Multiple risk factors,such as aging,mechanical overloading,trauma,overuse,etc.are involved in OA development.Several approaches have been utilized to repair cartilage defects.Among them,biomaterials-based mes-enchymal stromal cell(MSCs)therapy is considered as the most promising modality.The burgeoning material science and manufacturing technologies,such as 3D printing,allow us to mimic native articu-lar cartilage and regulate the artificial cartilage development,regeneration and functional restoration.In this review article,we will summarize the recent progress of biomaterials combined with MSCs or chon-drocytes in repairing cartilage damage induced by OA.Several typical natural and synthetic biomaterials,such as collagen,alginate,hyaluronic acid and poly(ethylene glycol),polylactide acid,polyurethane,etc.for cartilage repairing will be introduced.Moreover,critical signaling pathways associated with the pro-gression of OA,as well as the targeted pharmacologic,genetic therapies and tissue engineering scaffolds for OA and cartilage repairing are presented.We will also provide our prospects for future directions in this active research area.
基金supported by the Young Scientists Promotion Fund of Natural Science Foundation of Guangdong Province,National Natural Science Foundation of China(No.81703438)the Key R&D Program of Shandong Province(No.2021ZDSYS26)National Science and Technology Major Project of China(No.2018ZX09711001-001-013)+1 种基金CAMS Innovation Fund for Medical Sciences(No.2017-I2M-3-010)Student Innovation Training Program(No.201812121093)。
文摘Plastic and elastic behaviors of organic crystals have profound influence on the processability of pharmaceutical substances.Analogous to metals,the identifications of molecular slip planes in organic crystals are regarded as a strategy for harnessing plasticity.In this work,we experimentally characterized the form II anhydrous theophylline(THPa)and its monohydrate(THPm)for their distinct plastic and elastic behaviors.Extensive DFT calculations were performed to model the effects of increasing lattice strains on molecular packing.We discovered that the energy barrier associated with the strain-induced molecular rearrangement would link to the plasticity of THPa,and possibly other simple aromatic compounds.Meanwhile,water molecules in THPm disrupt the stacking architecture from THPm and effectively undermine the general mechanism for plasticity.Hydrate formation would therefore be an alternative strategy to engineer the mechanical property of organic crystalline materials.
文摘Osteoarthritis(OA)is a painful degenerative joint disease and is the leading cause of chronic disability among elderly individuals.To improve the quality of life for patients with OA,the primary goal for OA treatment is to relieve the pain.During OA progression,nerve ingrowth was observed in synovial tissue and articular cartilage.These abnormal neonatal nerves act as nociceptors to detect OA pain signals.The molecular mechanisms for transmitting OA pain in the joint tissues to the central nerve system(CNS)is currently unknown.MicroRNA miR-204 has been demonstrated to maintain the homeostasis of joint tissues and have chondro-protective effect on OA pathogenesis.However,the role of miR-204 in OA pain has not been determined.In this study,we investigated interactions between chondrocytes and neural cells and evaluated the effect and mechanism of miR-204 delivered by exosome in the treatment of OA pain in an experimental OA mouse model.Our findings demonstrated that miR-204 could protect OA pain by inhibition of SP1-LDL Receptor Related Protein 1(LRP1)signaling and blocking neuro-cartilage interaction in the joint.Our studies defined novel molecular targets for the treatment of OA pain.
