Bone and joint-related diseases,including osteoarthritis(OA),rheumatoid arthritis(RA),and bone tumors,pose significant health challenges due to their debilitating effects on the musculoskeletal system.14-3-3 proteins,...Bone and joint-related diseases,including osteoarthritis(OA),rheumatoid arthritis(RA),and bone tumors,pose significant health challenges due to their debilitating effects on the musculoskeletal system.14-3-3 proteins,a family of conserved regulatory molecules,play a critical role in the pathology of these diseases.This review discusses the intricate structure and multifunctionality of 14-3-3 proteins,their regulation of signaling pathways,and their interactions with other proteins.We underscore the significance of 14-3-3 proteins in the regulation of osteoblasts,osteoclasts,chondrocytes,and bone remodeling,all key factors in the maintenance and dysfunction of bone and joint systems.Specific focus is directed toward elucidating the contribution of 14-3-3proteins in the pathology of OA,RA,and bone malignancies,where dysregulated 14-3-3-mediated signaling cascades have been implicated in the disease processes.This review illuminates how the perturbation of 14-3-3 protein interactions can lead to the pathological manifestations observed in these disorders,including joint destruction and osteolytic activity.We highlight cuttingedge research that positions 14-3-3 proteins as potential biomarkers for disease progression and as innovative therapeutic targets,offering new avenues for disease intervention and management.展开更多
Bone tissue engineering is an exciting approach to directly repair bone defects or engineer bone tissue for transplantation.Biomaterials play a pivotal role in providing a template and extracellular environment to sup...Bone tissue engineering is an exciting approach to directly repair bone defects or engineer bone tissue for transplantation.Biomaterials play a pivotal role in providing a template and extracellular environment to support regenerative cells and promote tissue regeneration. A variety of signaling cues have been identified to regulate cellular activity, tissue development, and the healing process. Numerous studies and trials have shown the promise of tissue engineering, but successful translations of bone tissue engineering research into clinical applications have been limited, due in part to a lack of optimal delivery systems for these signals. Biomedical engineers are therefore highly motivated to develop biomimetic drug delivery systems, which benefit from mimicking signaling molecule release or presentation by the native extracellular matrix during development or the natural healing process. Engineered biomimetic drug delivery systems aim to provide control over the location, timing, and release kinetics of the signal molecules according to the drug's physiochemical properties and specific biological mechanisms. This article reviews biomimetic strategies in signaling delivery for bone tissue engineering, with a focus on delivery systems rather than specific molecules. Both fundamental considerations and specific design strategies are discussed with examples of recent research progress, demonstrating the significance and potential of biomimetic delivery systems for bone tissue engineering.展开更多
Carboxyl terminus of Hsp70-interacting protein（CHIP or STUB1） is an E3 ligase and regulates the stability of several proteins which are involved in different cellular functions. Our previous studies demonstrated tha...Carboxyl terminus of Hsp70-interacting protein（CHIP or STUB1） is an E3 ligase and regulates the stability of several proteins which are involved in different cellular functions. Our previous studies demonstrated that Chip deficient mice display bone loss phenotype due to increased osteoclast formation through enhancing TRAF6 activity in osteoclasts. In this study we provide novel evidence about the function of CHIP. We found that osteoblast differentiation and bone formation were also decreased in Chip KO mice. In bone marrow stromal（BMS） cells derived from Chip^-/- mice, expression of a panel of osteoblast marker genes was significantly decreased. ALP activity and mineralized bone matrix formation were also reduced in Chip-deficient BMS cells. We also found that in addition to the regulation of TRAF6, CHIP also inhibits TNFα-induced NF-κB signaling through promoting TRAF2 and TRAF5 degradation. Specific deletion of Chip in BMS cells downregulated expression of osteoblast marker genes which could be reversed by the addition of NF-κB inhibitor. These results demonstrate that the osteopenic phenotype observed in Chip^-/- mice was due to the combination of increased osteoclast formation and decreased osteoblast differentiation. Taken together, our findings indicate a significant role of CHIP in bone remodeling.展开更多
More than 500,000 bone grafting procedures are performed annually in the USA.Considering the significant limitations of available bone grafts,we previously invented a phase-separation technology to generate nano-fibro...More than 500,000 bone grafting procedures are performed annually in the USA.Considering the significant limitations of available bone grafts,we previously invented a phase-separation technology to generate nano-fibrous poly(L-lactic acid)(PLLA)scaffolds that mimic the bone matrix collagen in nanofiber geometry and enhance bone regeneration.Here we report the development of nanofibrous scaffolds with covalently attached synthetic peptides that mimic native collagen peptides to activate the two main collagen receptors in bone cells,discoidin domain receptor 2(DDR2)andβ1 integrins.We synthesized a PLLA-based graft-copolymer to enable covalent peptide conjugation via a click reaction.Using PLLA and the graft-copolymer,we developed 3D scaf-folds with interconnected pores and peptides-containing nanofibers to activate DDR2 andβ1 integrins of oste-ogenic cells.The degradation rate and mechanical properties of the scaffolds are tunable.The peptides-decorated nanofibrous scaffolds demonstrated 7.8 times more mineralized bone regeneration over the control scaffolds without the peptides in a critical-sized bone defect regeneration model after 8 weeks of implantation,showing a synergistic effect of the two peptides.This study demonstrates the power of scaffolds to mimic ECM at both nanometer and molecular levels,activating cell surface receptors to liberate the innate regenerative potential of host stem/progenitor cells.展开更多
Tissue engineering scaffolds play a vital role in regenerative medicine.It not only provides a temporary 3-dimensional support during tissue repair,but also regulates the cell behavior,such as cell adhesion,proliferat...Tissue engineering scaffolds play a vital role in regenerative medicine.It not only provides a temporary 3-dimensional support during tissue repair,but also regulates the cell behavior,such as cell adhesion,proliferation and differentiation.In this review,we summarize the development and trends of functional scaffolding biomaterials including electrically conducting hydrogels and nanocomposites of hydroxyapatite(HA)and bioactive glasses(BGs)with various biodegradable polymers.Furthermore,the progress on the fabrication of biomimetic nanofibrous scaffolds from conducting polymers and composites of HA and BG via electrospinning,deposition and thermally induced phase separation is discussed.Moreover,bioactive molecules and surface properties of scaffolds are very important during tissue repair.Bioactive molecule-releasing scaffolds and antimicrobial surface coatings for biomedical implants and scaffolds are also reviewed.展开更多
Native tissues possess unparalleled physiochemical and biological functions, which can be attributed to their hybrid polymer composition and intrinsic bioactivity. However, there are also various concerns or limitatio...Native tissues possess unparalleled physiochemical and biological functions, which can be attributed to their hybrid polymer composition and intrinsic bioactivity. However, there are also various concerns or limitations over the use of natural materials derived from animals or cadavers, including the potential immunogenicity, pathogen transmission, batch to batch consistence and mismatch in properties for various applications. Therefore, there is an increasing interest in developing degradable hybrid polymer biomaterials with controlled properties for highly efficient biomedical applications. There have been efforts to mimic the extracellular protein structure such as nanofibrous and composite scaffolds, to functionalize scaffold surface for improved cellular interaction, to incorporate controlled biomolecule release capacity to impart biological signaling, and to vary physical properties of scaffolds to regulate cellular behavior. In this review, we highlight the design and synthesis of degradable hybrid polymer biomaterials and focus on recent developments in osteoconductive, elastomeric, photoluminescent and electroactive hybrid polymers. The review further exemplifies their applications for bone tissue regeneration.展开更多
基金supported by NIH research grants R01AR062207,R01AR061484,R01AR076900,R01AR078035,and R01NS070328。
文摘Bone and joint-related diseases,including osteoarthritis(OA),rheumatoid arthritis(RA),and bone tumors,pose significant health challenges due to their debilitating effects on the musculoskeletal system.14-3-3 proteins,a family of conserved regulatory molecules,play a critical role in the pathology of these diseases.This review discusses the intricate structure and multifunctionality of 14-3-3 proteins,their regulation of signaling pathways,and their interactions with other proteins.We underscore the significance of 14-3-3 proteins in the regulation of osteoblasts,osteoclasts,chondrocytes,and bone remodeling,all key factors in the maintenance and dysfunction of bone and joint systems.Specific focus is directed toward elucidating the contribution of 14-3-3proteins in the pathology of OA,RA,and bone malignancies,where dysregulated 14-3-3-mediated signaling cascades have been implicated in the disease processes.This review illuminates how the perturbation of 14-3-3 protein interactions can lead to the pathological manifestations observed in these disorders,including joint destruction and osteolytic activity.We highlight cuttingedge research that positions 14-3-3 proteins as potential biomarkers for disease progression and as innovative therapeutic targets,offering new avenues for disease intervention and management.
基金supported by the US DOD(W81XWH-12-2-0008)the National Institutes of Health(DE022327,HL136231,TR001711)the National Natural Science Foundation of China(Grant No.31470915)
文摘Bone tissue engineering is an exciting approach to directly repair bone defects or engineer bone tissue for transplantation.Biomaterials play a pivotal role in providing a template and extracellular environment to support regenerative cells and promote tissue regeneration. A variety of signaling cues have been identified to regulate cellular activity, tissue development, and the healing process. Numerous studies and trials have shown the promise of tissue engineering, but successful translations of bone tissue engineering research into clinical applications have been limited, due in part to a lack of optimal delivery systems for these signals. Biomedical engineers are therefore highly motivated to develop biomimetic drug delivery systems, which benefit from mimicking signaling molecule release or presentation by the native extracellular matrix during development or the natural healing process. Engineered biomimetic drug delivery systems aim to provide control over the location, timing, and release kinetics of the signal molecules according to the drug's physiochemical properties and specific biological mechanisms. This article reviews biomimetic strategies in signaling delivery for bone tissue engineering, with a focus on delivery systems rather than specific molecules. Both fundamental considerations and specific design strategies are discussed with examples of recent research progress, demonstrating the significance and potential of biomimetic delivery systems for bone tissue engineering.
基金supported by National Institutes of Health Grants, R01 AR054465, R01 AR070222, and R01 AR070222supported by the grants of Natural Science Foundation of China (NSFC) to TW (grants No. 81301531 and 81572104)+1 种基金supported by the grant from Shenzhen Science and Technology Innovation Committee, China (grant No. JCYJ20160331114205502)the grant from Shenzhen Development and Reform Committee, China for Shenzhen Engineering Laboratory of Orthopedic Regenerative Technologies
文摘Carboxyl terminus of Hsp70-interacting protein（CHIP or STUB1） is an E3 ligase and regulates the stability of several proteins which are involved in different cellular functions. Our previous studies demonstrated that Chip deficient mice display bone loss phenotype due to increased osteoclast formation through enhancing TRAF6 activity in osteoclasts. In this study we provide novel evidence about the function of CHIP. We found that osteoblast differentiation and bone formation were also decreased in Chip KO mice. In bone marrow stromal（BMS） cells derived from Chip^-/- mice, expression of a panel of osteoblast marker genes was significantly decreased. ALP activity and mineralized bone matrix formation were also reduced in Chip-deficient BMS cells. We also found that in addition to the regulation of TRAF6, CHIP also inhibits TNFα-induced NF-κB signaling through promoting TRAF2 and TRAF5 degradation. Specific deletion of Chip in BMS cells downregulated expression of osteoblast marker genes which could be reversed by the addition of NF-κB inhibitor. These results demonstrate that the osteopenic phenotype observed in Chip^-/- mice was due to the combination of increased osteoclast formation and decreased osteoblast differentiation. Taken together, our findings indicate a significant role of CHIP in bone remodeling.
基金financial support from Department of Defense(DoD W81XWH-20-1-0572:PXM,W81XWH-20-1-0571:RTF)National Institutes of Health(NIH R01DE029465:RTF and R01AR075770:PXM)。
文摘More than 500,000 bone grafting procedures are performed annually in the USA.Considering the significant limitations of available bone grafts,we previously invented a phase-separation technology to generate nano-fibrous poly(L-lactic acid)(PLLA)scaffolds that mimic the bone matrix collagen in nanofiber geometry and enhance bone regeneration.Here we report the development of nanofibrous scaffolds with covalently attached synthetic peptides that mimic native collagen peptides to activate the two main collagen receptors in bone cells,discoidin domain receptor 2(DDR2)andβ1 integrins.We synthesized a PLLA-based graft-copolymer to enable covalent peptide conjugation via a click reaction.Using PLLA and the graft-copolymer,we developed 3D scaf-folds with interconnected pores and peptides-containing nanofibers to activate DDR2 andβ1 integrins of oste-ogenic cells.The degradation rate and mechanical properties of the scaffolds are tunable.The peptides-decorated nanofibrous scaffolds demonstrated 7.8 times more mineralized bone regeneration over the control scaffolds without the peptides in a critical-sized bone defect regeneration model after 8 weeks of implantation,showing a synergistic effect of the two peptides.This study demonstrates the power of scaffolds to mimic ECM at both nanometer and molecular levels,activating cell surface receptors to liberate the innate regenerative potential of host stem/progenitor cells.
基金The authors gratefully acknowledge the financial support of the US National Institutes of Health(NIDCR DE015384,DE017689,DE022327),DOD(W81XWH-12-2-0008)the National Science Foundation of the United States(DMR-1206575)the National Natural Science Foundation of China(21304073 and 51403173).
文摘Tissue engineering scaffolds play a vital role in regenerative medicine.It not only provides a temporary 3-dimensional support during tissue repair,but also regulates the cell behavior,such as cell adhesion,proliferation and differentiation.In this review,we summarize the development and trends of functional scaffolding biomaterials including electrically conducting hydrogels and nanocomposites of hydroxyapatite(HA)and bioactive glasses(BGs)with various biodegradable polymers.Furthermore,the progress on the fabrication of biomimetic nanofibrous scaffolds from conducting polymers and composites of HA and BG via electrospinning,deposition and thermally induced phase separation is discussed.Moreover,bioactive molecules and surface properties of scaffolds are very important during tissue repair.Bioactive molecule-releasing scaffolds and antimicrobial surface coatings for biomedical implants and scaffolds are also reviewed.
基金US DOD (No.W81XWH-12-2-0008)the National Institutes of Health (Nos.NIDCR DE022327 and T32 HD007505)+1 种基金National Natural Science Foundation of China (Nos.51502237,21304073,and 51673155)and Xi'an Jiaotong University.
文摘Native tissues possess unparalleled physiochemical and biological functions, which can be attributed to their hybrid polymer composition and intrinsic bioactivity. However, there are also various concerns or limitations over the use of natural materials derived from animals or cadavers, including the potential immunogenicity, pathogen transmission, batch to batch consistence and mismatch in properties for various applications. Therefore, there is an increasing interest in developing degradable hybrid polymer biomaterials with controlled properties for highly efficient biomedical applications. There have been efforts to mimic the extracellular protein structure such as nanofibrous and composite scaffolds, to functionalize scaffold surface for improved cellular interaction, to incorporate controlled biomolecule release capacity to impart biological signaling, and to vary physical properties of scaffolds to regulate cellular behavior. In this review, we highlight the design and synthesis of degradable hybrid polymer biomaterials and focus on recent developments in osteoconductive, elastomeric, photoluminescent and electroactive hybrid polymers. The review further exemplifies their applications for bone tissue regeneration.
