Emerging insights into cellular senescence highlight the relevance of senescence in musculoskeletal disorders,which represent the leading global cause of disability.Cellular senescence was initially described by Hayfl...Emerging insights into cellular senescence highlight the relevance of senescence in musculoskeletal disorders,which represent the leading global cause of disability.Cellular senescence was initially described by Hayflick et al.in 1961 as an irreversible nondividing state in in vitro cell culture studies.We now know that cellular senescence can occur in vivo in response to various stressors as a heterogeneous and tissue-specific cell state with a secretome phenotype acquired after the initial growth arrest.In the past two decades,compelling evidence from preclinical models and human data show an accumulation of senescent cells in many components of the musculoskeletal system.Cellular senescence is therefore a defining feature of age-related musculoskeletal disorders,and targeted elimination of these cells has emerged recently as a promising therapeutic approach to ameliorate tissue damage and promote repair and regeneration of the skeleton and skeletal muscles.In this review,we summarize evidence of the role of senescent cells in the maintenance of bone homeostasis during childhood and their contribution to the pathogenesis of chronic musculoskeletal disorders,including osteoporosis,osteoarthritis,and sarcopenia.We highlight the diversity of the senescent cells in the microenvironment of bone,joint,and skeletal muscle tissue,as well as the mechanisms by which these senescent cells are involved in musculoskeletal diseases.In addition,we discuss how identifying and targeting senescent cells might positively affect pathologic progression and musculoskeletal system regeneration.展开更多
Composite biomaterials comprising polylactide(PLA)and hydroxyapatite(HA)are applied in bone,cartilage and dental regenerative medicine,where HA confers osteoconductive properties.However,after surgical implantation,ad...Composite biomaterials comprising polylactide(PLA)and hydroxyapatite(HA)are applied in bone,cartilage and dental regenerative medicine,where HA confers osteoconductive properties.However,after surgical implantation,adverse immune responses to these composites can occur,which have been attributed to size and morphology of HA particles.Approaches to effectively modulate these adverse immune responses have not been described.PLA degradation products have been shown to alter immune cell metabolism(immunometabolism),which drives the inflammatory response.Accordingly,to modulate the inflammatory response to composite biomaterials,inhibitors were incorporated into composites comprised of amorphous PLA(aPLA)and HA(aPLA+HA)to regulate glycolytic flux.Inhibition at specific steps in glycolysis reduced proinflammatory(CD86+CD206-)and increased pro-regenerative(CD206+)immune cell populations around implanted aPLA+HA.Notably,neutrophil and dendritic cell(DC)numbers along with proinflammatory monocyte and macrophage populations were decreased,and Arginase 1 expression among DCs was increased.Targeting immunometabolism to control the proinflammatory response to biomaterial composites,thereby creating a pro-regenerative microenvironment,is a significant advance in tissue engineering where immunomodulation enhances osseointegration and angiogenesis,which could lead to improved bone regeneration.展开更多
基金This work was supported by the National Institutes of Health grant R01 AG068226 and R01AG072090 to M.W.and P01AG066603 to X.C.
文摘Emerging insights into cellular senescence highlight the relevance of senescence in musculoskeletal disorders,which represent the leading global cause of disability.Cellular senescence was initially described by Hayflick et al.in 1961 as an irreversible nondividing state in in vitro cell culture studies.We now know that cellular senescence can occur in vivo in response to various stressors as a heterogeneous and tissue-specific cell state with a secretome phenotype acquired after the initial growth arrest.In the past two decades,compelling evidence from preclinical models and human data show an accumulation of senescent cells in many components of the musculoskeletal system.Cellular senescence is therefore a defining feature of age-related musculoskeletal disorders,and targeted elimination of these cells has emerged recently as a promising therapeutic approach to ameliorate tissue damage and promote repair and regeneration of the skeleton and skeletal muscles.In this review,we summarize evidence of the role of senescent cells in the maintenance of bone homeostasis during childhood and their contribution to the pathogenesis of chronic musculoskeletal disorders,including osteoporosis,osteoarthritis,and sarcopenia.We highlight the diversity of the senescent cells in the microenvironment of bone,joint,and skeletal muscle tissue,as well as the mechanisms by which these senescent cells are involved in musculoskeletal diseases.In addition,we discuss how identifying and targeting senescent cells might positively affect pathologic progression and musculoskeletal system regeneration.
基金Funding for this work was provided in part by the James and Kathleen Cornelius Endowment at MSU.The Mass Spectrometry core at MSU,especially A.J.Schilmiller and J.O’Keefe,helped to analyze releasates.
文摘Composite biomaterials comprising polylactide(PLA)and hydroxyapatite(HA)are applied in bone,cartilage and dental regenerative medicine,where HA confers osteoconductive properties.However,after surgical implantation,adverse immune responses to these composites can occur,which have been attributed to size and morphology of HA particles.Approaches to effectively modulate these adverse immune responses have not been described.PLA degradation products have been shown to alter immune cell metabolism(immunometabolism),which drives the inflammatory response.Accordingly,to modulate the inflammatory response to composite biomaterials,inhibitors were incorporated into composites comprised of amorphous PLA(aPLA)and HA(aPLA+HA)to regulate glycolytic flux.Inhibition at specific steps in glycolysis reduced proinflammatory(CD86+CD206-)and increased pro-regenerative(CD206+)immune cell populations around implanted aPLA+HA.Notably,neutrophil and dendritic cell(DC)numbers along with proinflammatory monocyte and macrophage populations were decreased,and Arginase 1 expression among DCs was increased.Targeting immunometabolism to control the proinflammatory response to biomaterial composites,thereby creating a pro-regenerative microenvironment,is a significant advance in tissue engineering where immunomodulation enhances osseointegration and angiogenesis,which could lead to improved bone regeneration.
