Osteoarthritis(OA),long considered a primary disorder of articular cartilage,is commonly associated with subchondral bone sclerosis.However,the cellular mechanisms responsible for changes to subchondral bone in OA,and...Osteoarthritis(OA),long considered a primary disorder of articular cartilage,is commonly associated with subchondral bone sclerosis.However,the cellular mechanisms responsible for changes to subchondral bone in OA,and the extent to which these changes are drivers of or a secondary reaction to cartilage degeneration,remain unclear.In knee joints from human patients with end-stage OA,we found evidence of profound defects in osteocyte function.Suppression of osteocyte perilacunar/canalicular remodeling(PLR)was most severe in the medial compartment of OA subchondral bone,with lower protease expression,diminished canalicular networks,and disorganized and hypermineralized extracellular matrix.As a step toward evaluating the causality of PLR suppression in OA,we ablated the PLR enzyme MMP13 in osteocytes while leaving chondrocytic MMP13 intact,using Cre recombinase driven by the 9.6-kb DMP1 promoter.Not only did osteocytic MMP13 deficiency suppress PLR in cortical and subchondral bone,but it also compromised cartilage.Even in the absence of injury,osteocytic MMP13 deficiency was sufficient to reduce cartilage proteoglycan content,change chondrocyte production of collagen II,aggrecan,and MMP13,and increase the incidence of cartilage lesions,consistent with early OA.Thus,in humans and mice,defects in PLR coincide with cartilage defects.Osteocyte-derived MMP13 emerges as a critical regulator of cartilage homeostasis,likely via its effects on PLR.Together,these findings implicate osteocytes in bone-cartilage crosstalk in the joint and suggest a causal role for suppressed perilacunar/canalicular remodeling in osteoarthritis.展开更多
Osteoarthritis(OA)is an aging-associated disease characterized by joint stiffness pain and destroyed articular cartilage.Traditional treatments for OA are limited to alleviating various OA symptoms.There is a lack of ...Osteoarthritis(OA)is an aging-associated disease characterized by joint stiffness pain and destroyed articular cartilage.Traditional treatments for OA are limited to alleviating various OA symptoms.There is a lack of drugs available in clinical practice that can truly repair cartilage damage.Here,we developed the chondroitin sulfate analog CS-semi5,semi-synthesized from chondroitin sulfate A.In vivo,CS-semi5 alleviated inflammation,provided analgesic effects,and protected cartilage in the modified Hulth OA rat model and papain-induced OA rat model.A bioinformatics analysis was performed on samples from OA patients and an exosome analysis on papain-induced OA rats,revealing miR-122-5p as the key regulator associated with CS-semi5 in OA treatment.Binding prediction revealed that miR-122-5p acted on the 30-untranslated region of p38 mitogen-activated protein kinase,which was related to MMP13 regulation.Subsequent in vitro experiments revealed that CS-semi5 effectively reduced cartilage degeneration and maintained matrix homeostasis by inhibiting matrix breakdown through the miR-122-5p/p38/MMP13 axis,which was further validated in the articular cartilage of OA rats.This is the first study to investigate the semi-synthesized chondroitin sulfate CS-semi5,revealing its cartilageprotecting,anti-inflammatory,and analgesic properties that show promising therapeutic effects in OA via the miR-122-5p/p38/MMP13 pathway.展开更多
Posttraumatic osteoarthritis(PTOA)patients are often diagnosed by X-ray imaging at a middle-late stage when drug interventions are less effective.Early PTOA is characterized by overexpressed matrix metalloprotease 13(...Posttraumatic osteoarthritis(PTOA)patients are often diagnosed by X-ray imaging at a middle-late stage when drug interventions are less effective.Early PTOA is characterized by overexpressed matrix metalloprotease 13(MMP13).Herein,we constructed an integrated diagnosis and treatment micelle modified with MMP13 enzyme-detachable,cyanine 5(Cy5)-containing PEG,black hole quencher-3(BHQ3),and cRGD ligands and loaded with siRNA silencing MMP13(siM13),namely ERMs@siM13.ERMs@siM13 could be cleaved by MMP13 in the diseased cartilage tissues to detach the PEG shell,causing cRGD exposure.Accordingly,the ligand exposure promoted micelle uptake by the diseased chondrocytes by binding to cell surfaceαvβ3 integrin,increasing intracellular siM13 delivery for on-demand MMP13 downregulation.Meanwhile,the Cy5 fluorescence was restored by detaching from the BHQ3-containing micelle,precisely reflecting the diseased cartilage state.In particular,the intensity of Cy5 fluorescence generated by ERMs@siM13 that hinged on the MMP13 levels could reflect the PTOA severity,enabling the physicians to adjust the therapeutic regimen.Finally,in the murine PTOA model,ERMs@siM13 could diagnose the early-stage PTOA,perform timely interventions,and monitor the OA progression level during treatment through a real-time detection of MMP13.Therefore,ERMs@siM13 represents an appealing approach for early-stage PTOA theranostics.展开更多
Objective:To observe the differences in clinical effect on knee osteoarthritis(KOA)between the holistic stratification acupotomy and the joint injection with sodium hyaluronate so as to provide a safe and effective tr...Objective:To observe the differences in clinical effect on knee osteoarthritis(KOA)between the holistic stratification acupotomy and the joint injection with sodium hyaluronate so as to provide a safe and effective treatment for KOA.Methods:A total of 100 KOA patients were randomly divided into an acupotomy group and a sodium hyaluronate group,50 patients in each one.In the acupotomy group,the holistic stratification acupotomy was adopted.In the sodium hyaluronate group,sodium hyaluronate injection was applied in the joints.The index of Western Ontario and McMaster University(WOMAC)and the expressions of MMP1 and MMP13 in bursal fluid of the patients were compared before and after treatment in the patients between two groups before and after treatment,and the clinical therapeutic effect was observed.Results:After treatment,WOMAC score of each dimension and the concentrations of MMP1 and MMP13 in bursal fluid of the patients of either group were all lower than those before treatment(all P<0.05).After treatment,WOMAC score of each dimension and the concentrations of MMP1 and MMP13 in bursal fluid in the acupotomy group were lower than the sodium hyaluronate group(all P<0.05).The total effective rate in the acupotomy group was higher than that of the sodium hyaluronate group(P<0.05).Conclusion:Both the holistic stratification acupotomy and the joint injection with sodium hyaluronate are effective on KOA in this trial.However,the therapeutic effect of holistic stratification acupotomy is remarkable,which is probably related to the improvements in inflammatory response.展开更多
基金supported by the National Institute of Dental and Craniofacial Research (R01 DE019284)the Department of Defense (OR130191)+1 种基金the Read Research Foundation, the National Science Foundation (GRFP 1650113 and CDMI)the National Institute of Arthritis and Musculoskeletal and Skin Diseases (P30 AR06626201)
文摘Osteoarthritis(OA),long considered a primary disorder of articular cartilage,is commonly associated with subchondral bone sclerosis.However,the cellular mechanisms responsible for changes to subchondral bone in OA,and the extent to which these changes are drivers of or a secondary reaction to cartilage degeneration,remain unclear.In knee joints from human patients with end-stage OA,we found evidence of profound defects in osteocyte function.Suppression of osteocyte perilacunar/canalicular remodeling(PLR)was most severe in the medial compartment of OA subchondral bone,with lower protease expression,diminished canalicular networks,and disorganized and hypermineralized extracellular matrix.As a step toward evaluating the causality of PLR suppression in OA,we ablated the PLR enzyme MMP13 in osteocytes while leaving chondrocytic MMP13 intact,using Cre recombinase driven by the 9.6-kb DMP1 promoter.Not only did osteocytic MMP13 deficiency suppress PLR in cortical and subchondral bone,but it also compromised cartilage.Even in the absence of injury,osteocytic MMP13 deficiency was sufficient to reduce cartilage proteoglycan content,change chondrocyte production of collagen II,aggrecan,and MMP13,and increase the incidence of cartilage lesions,consistent with early OA.Thus,in humans and mice,defects in PLR coincide with cartilage defects.Osteocyte-derived MMP13 emerges as a critical regulator of cartilage homeostasis,likely via its effects on PLR.Together,these findings implicate osteocytes in bone-cartilage crosstalk in the joint and suggest a causal role for suppressed perilacunar/canalicular remodeling in osteoarthritis.
基金supported by CAMS Innovation Fund for Medical Sciences(2022-I2M-2-002 and 2022-I2M-1e014,China)the Non-Profit Central Research Institute Fund of Chinese Academy of Medical Sciences(2020-JKCS-019,China).
文摘Osteoarthritis(OA)is an aging-associated disease characterized by joint stiffness pain and destroyed articular cartilage.Traditional treatments for OA are limited to alleviating various OA symptoms.There is a lack of drugs available in clinical practice that can truly repair cartilage damage.Here,we developed the chondroitin sulfate analog CS-semi5,semi-synthesized from chondroitin sulfate A.In vivo,CS-semi5 alleviated inflammation,provided analgesic effects,and protected cartilage in the modified Hulth OA rat model and papain-induced OA rat model.A bioinformatics analysis was performed on samples from OA patients and an exosome analysis on papain-induced OA rats,revealing miR-122-5p as the key regulator associated with CS-semi5 in OA treatment.Binding prediction revealed that miR-122-5p acted on the 30-untranslated region of p38 mitogen-activated protein kinase,which was related to MMP13 regulation.Subsequent in vitro experiments revealed that CS-semi5 effectively reduced cartilage degeneration and maintained matrix homeostasis by inhibiting matrix breakdown through the miR-122-5p/p38/MMP13 axis,which was further validated in the articular cartilage of OA rats.This is the first study to investigate the semi-synthesized chondroitin sulfate CS-semi5,revealing its cartilageprotecting,anti-inflammatory,and analgesic properties that show promising therapeutic effects in OA via the miR-122-5p/p38/MMP13 pathway.
基金supported by Integrated Project of Major Research Plan of National Natural Science Foundation of China (92249303)National Natural Science Foundation of China (82230071,82172098,82371603,82102217,81872428,and 81703010)+7 种基金the Shanghai Rising Star Program (21QA1412000)Shanghai Hospital Development Center (SHDC2023CRT013)Shanghai Committee of Science and Technology (23141900600,Laboratory Animal Research Project)Shanghai Baoshan District Medical Health Project (21-E-14)the Construction of Key Medical Disciplines of Baoshan District of Shanghai (BSZK-2023-Z07)the Shanghai Municipal Natural Science Foundation (23ZR1463300)Postdoctoral Fellowship Program of CPSF (GZB20230397)General Funding for China Postdoctoral Science Foundation (2023M732179).
文摘Posttraumatic osteoarthritis(PTOA)patients are often diagnosed by X-ray imaging at a middle-late stage when drug interventions are less effective.Early PTOA is characterized by overexpressed matrix metalloprotease 13(MMP13).Herein,we constructed an integrated diagnosis and treatment micelle modified with MMP13 enzyme-detachable,cyanine 5(Cy5)-containing PEG,black hole quencher-3(BHQ3),and cRGD ligands and loaded with siRNA silencing MMP13(siM13),namely ERMs@siM13.ERMs@siM13 could be cleaved by MMP13 in the diseased cartilage tissues to detach the PEG shell,causing cRGD exposure.Accordingly,the ligand exposure promoted micelle uptake by the diseased chondrocytes by binding to cell surfaceαvβ3 integrin,increasing intracellular siM13 delivery for on-demand MMP13 downregulation.Meanwhile,the Cy5 fluorescence was restored by detaching from the BHQ3-containing micelle,precisely reflecting the diseased cartilage state.In particular,the intensity of Cy5 fluorescence generated by ERMs@siM13 that hinged on the MMP13 levels could reflect the PTOA severity,enabling the physicians to adjust the therapeutic regimen.Finally,in the murine PTOA model,ERMs@siM13 could diagnose the early-stage PTOA,perform timely interventions,and monitor the OA progression level during treatment through a real-time detection of MMP13.Therefore,ERMs@siM13 represents an appealing approach for early-stage PTOA theranostics.
基金Supported by Youth Science Foundation of National Natural Science Foundation of China:81,704,195Research Project of Integrated Traditional Chinese and Western Medicine of Tianjin Health Commission:015,018。
文摘Objective:To observe the differences in clinical effect on knee osteoarthritis(KOA)between the holistic stratification acupotomy and the joint injection with sodium hyaluronate so as to provide a safe and effective treatment for KOA.Methods:A total of 100 KOA patients were randomly divided into an acupotomy group and a sodium hyaluronate group,50 patients in each one.In the acupotomy group,the holistic stratification acupotomy was adopted.In the sodium hyaluronate group,sodium hyaluronate injection was applied in the joints.The index of Western Ontario and McMaster University(WOMAC)and the expressions of MMP1 and MMP13 in bursal fluid of the patients were compared before and after treatment in the patients between two groups before and after treatment,and the clinical therapeutic effect was observed.Results:After treatment,WOMAC score of each dimension and the concentrations of MMP1 and MMP13 in bursal fluid of the patients of either group were all lower than those before treatment(all P<0.05).After treatment,WOMAC score of each dimension and the concentrations of MMP1 and MMP13 in bursal fluid in the acupotomy group were lower than the sodium hyaluronate group(all P<0.05).The total effective rate in the acupotomy group was higher than that of the sodium hyaluronate group(P<0.05).Conclusion:Both the holistic stratification acupotomy and the joint injection with sodium hyaluronate are effective on KOA in this trial.However,the therapeutic effect of holistic stratification acupotomy is remarkable,which is probably related to the improvements in inflammatory response.