Toll-like receptor （TLR）-mediated inflammatory response could negatively affect bone metabolism. In this study, we determined how osteogenesis is regulated during inflammatory responses that are downstream of TLR si...Toll-like receptor （TLR）-mediated inflammatory response could negatively affect bone metabolism. In this study, we determined how osteogenesis is regulated during inflammatory responses that are downstream of TLR signaling. Human primary osteoblasts were cultured in collagen gels. Pam3CSK4 （P3C） and Escherichia coli lipopolysaccharide （EcLPS） were used as TLR2 and TLR4 ligand respectively. Porphyromonas gingivalis LPS having TLR2 activity with either TLR4 agonism （Pg1690） or TLR4 antagonism （Pg1449） and mutant E. coli LPS （LPxE/LPxF/WSK） were used. IL-lp, SH2-containing inositol phosphatase-1 （SHIP1） that has regulatory roles in osteogenesis, alkaline phosphatase and mineralization were analyzed. 3α-Aminocholestane （3AC） was used to inhibit SHIP1. Our results suggest that osteoblasts stimulated by P3C, poorly induced IL-1β but strongly upregulated SHIP1 and enhanced osteogenic mediators. On the contrary, EcLPS significantly induced IL-1β and osteogenic mediators were not induced. While Pg1690 downmodulated osteogenic mediators, Pg1449 enhanced osteogenic responses, suggesting that TLR4 signaling annuls osteogenesis even with TLR2 activity. Interestingly, mutant E. coli LPS that induces weak inflammation upregulated osteogenesis, but SHIP1 was not induced. Moreover, inhibiting SHIP1 significantly upregulated TLR2-mediated inflammatory response and downmodulated osteogenesis. In conclusion, these results suggest that induction of weak inflammatory response through TLR2 （with SHIP1 activity） and mutant TLR4 ligands could enhance osteogenesis.展开更多
激素性股骨头坏死(steroid-induced necrosis of the femoral head, SNOFH)是骨科常见难治性疾病,又被视为“不死癌症”,若不及时干预将导致患者面临人工全髋关节置换术的风险。近些年研究证实,“成骨-成血管耦联”途径研究SNOFH发生发...激素性股骨头坏死(steroid-induced necrosis of the femoral head, SNOFH)是骨科常见难治性疾病,又被视为“不死癌症”,若不及时干预将导致患者面临人工全髋关节置换术的风险。近些年研究证实,“成骨-成血管耦联”途径研究SNOFH发生发展的机制具有重要意义。SNOFH中医病机责之于脾肾亏虚为本,瘀血为病,痰阻为渐,毒聚为损。“成骨-成血管耦联”机制与“瘀去-新生-骨合”中医理论存在高度契合性。越来越多的临床证据表明中医药治疗SNOFH不仅具有疗效显著、不良反应小、价格低廉等优势,还能提高患者生存质量,为促进股骨头血管重建与再生以及股骨头坏死骨修复等发挥重要作用。基于“瘀去-新生-骨合”理论,临床上多采用补肾活血类中药及中药复方用于SNOFH防治,运用“成骨”之健脾补肾药,“成血管”之活血化瘀药,祛除“抑制因素”之化痰药、祛湿药,有步骤、有层次的治疗SNOFH取得显著效果。因此,从“成骨-成血管耦联”角度探讨SNOFH中医药干预的科学内涵已成为当今研究新热点,能够为后续SNOFH的防治研究和新药研发提供理论参考和借鉴。展开更多
背景:除了铁络合作用外,去铁胺还被认为是一种有效的低氧模拟剂及缺氧诱导因子1α稳定剂,近年的基础及临床研究中去铁胺也表现出良好的骨再生效应。去铁胺溶液或负载去铁胺的生物支架被局部应用于骨组织工程中,其对骨再生的促进涉及多...背景:除了铁络合作用外,去铁胺还被认为是一种有效的低氧模拟剂及缺氧诱导因子1α稳定剂,近年的基础及临床研究中去铁胺也表现出良好的骨再生效应。去铁胺溶液或负载去铁胺的生物支架被局部应用于骨组织工程中,其对骨再生的促进涉及多种功能特性及分子机制,但尚未完全明确,且其在骨再生中的研究进展缺乏有效总结。目的:对去铁胺应用于骨再生的功能特性、优缺点及其在基础研究及临床实践中的进展进行综述,以期为后续相关研究提供参考及策略。方法:以“deferoxamine OR desferrioxamine OR desferal OR DFO”“bone tissue engineering OR bone regeneration OR bone remodeling OR bone repair OR bone healing OR osteogenesis”“angiogenesis OR vascularized bone regeneration OR angiogenic-osteogenic coupling”为英文检索词检索PubMed数据库,以“去铁胺”“骨组织工程,骨再生,骨重建,骨修复,骨愈合”“成血管,血管化成骨,成骨-成血管偶联”为中文检索词检索万方和中国知网数据库,最终纳入88篇文献进行综述。结果与结论:①去铁胺能招募干细胞并调节干细胞功能,激活相关信号通路提高细胞的低氧适应能力,发挥抗炎抗氧化特性改善局部炎性环境,并通过偶联成骨-成血管及抑制骨吸收来促进骨再生。②相较于传统骨组织工程中加载的生长因子或多肽,去铁胺作为小分子药物具有独特的优势,同时也存在毒性反应及应用局限,因此优化载药形式及剂量是必要的。③去铁胺独特的成血管-成骨偶联能力,在不同类型的骨损伤如骨折、骨坏死、牵张成骨、骨移植、口腔相关成骨及骨缺损中,因对骨愈合过程中血管生成的加强而更能适应和解决复杂多变的临床情况及个体差异下造成的骨修复困难;但同时也需要对去铁胺的应用方式及安全剂量加以对比和优化,利于其应用范围的扩大及临床价值的提升。展开更多
基金supported by Elam M. and Georgina E.Hack Memorial Research Funds,Department of Periodontics,University of Washington,Seattle,WA,USAsupported by WVCTSI funds,West Virginia University,Morgantown,WV,USA
文摘Toll-like receptor （TLR）-mediated inflammatory response could negatively affect bone metabolism. In this study, we determined how osteogenesis is regulated during inflammatory responses that are downstream of TLR signaling. Human primary osteoblasts were cultured in collagen gels. Pam3CSK4 （P3C） and Escherichia coli lipopolysaccharide （EcLPS） were used as TLR2 and TLR4 ligand respectively. Porphyromonas gingivalis LPS having TLR2 activity with either TLR4 agonism （Pg1690） or TLR4 antagonism （Pg1449） and mutant E. coli LPS （LPxE/LPxF/WSK） were used. IL-lp, SH2-containing inositol phosphatase-1 （SHIP1） that has regulatory roles in osteogenesis, alkaline phosphatase and mineralization were analyzed. 3α-Aminocholestane （3AC） was used to inhibit SHIP1. Our results suggest that osteoblasts stimulated by P3C, poorly induced IL-1β but strongly upregulated SHIP1 and enhanced osteogenic mediators. On the contrary, EcLPS significantly induced IL-1β and osteogenic mediators were not induced. While Pg1690 downmodulated osteogenic mediators, Pg1449 enhanced osteogenic responses, suggesting that TLR4 signaling annuls osteogenesis even with TLR2 activity. Interestingly, mutant E. coli LPS that induces weak inflammation upregulated osteogenesis, but SHIP1 was not induced. Moreover, inhibiting SHIP1 significantly upregulated TLR2-mediated inflammatory response and downmodulated osteogenesis. In conclusion, these results suggest that induction of weak inflammatory response through TLR2 （with SHIP1 activity） and mutant TLR4 ligands could enhance osteogenesis.
文摘激素性股骨头坏死(steroid-induced necrosis of the femoral head, SNOFH)是骨科常见难治性疾病,又被视为“不死癌症”,若不及时干预将导致患者面临人工全髋关节置换术的风险。近些年研究证实,“成骨-成血管耦联”途径研究SNOFH发生发展的机制具有重要意义。SNOFH中医病机责之于脾肾亏虚为本,瘀血为病,痰阻为渐,毒聚为损。“成骨-成血管耦联”机制与“瘀去-新生-骨合”中医理论存在高度契合性。越来越多的临床证据表明中医药治疗SNOFH不仅具有疗效显著、不良反应小、价格低廉等优势,还能提高患者生存质量,为促进股骨头血管重建与再生以及股骨头坏死骨修复等发挥重要作用。基于“瘀去-新生-骨合”理论,临床上多采用补肾活血类中药及中药复方用于SNOFH防治,运用“成骨”之健脾补肾药,“成血管”之活血化瘀药,祛除“抑制因素”之化痰药、祛湿药,有步骤、有层次的治疗SNOFH取得显著效果。因此,从“成骨-成血管耦联”角度探讨SNOFH中医药干预的科学内涵已成为当今研究新热点,能够为后续SNOFH的防治研究和新药研发提供理论参考和借鉴。
文摘背景:除了铁络合作用外,去铁胺还被认为是一种有效的低氧模拟剂及缺氧诱导因子1α稳定剂,近年的基础及临床研究中去铁胺也表现出良好的骨再生效应。去铁胺溶液或负载去铁胺的生物支架被局部应用于骨组织工程中,其对骨再生的促进涉及多种功能特性及分子机制,但尚未完全明确,且其在骨再生中的研究进展缺乏有效总结。目的:对去铁胺应用于骨再生的功能特性、优缺点及其在基础研究及临床实践中的进展进行综述,以期为后续相关研究提供参考及策略。方法:以“deferoxamine OR desferrioxamine OR desferal OR DFO”“bone tissue engineering OR bone regeneration OR bone remodeling OR bone repair OR bone healing OR osteogenesis”“angiogenesis OR vascularized bone regeneration OR angiogenic-osteogenic coupling”为英文检索词检索PubMed数据库,以“去铁胺”“骨组织工程,骨再生,骨重建,骨修复,骨愈合”“成血管,血管化成骨,成骨-成血管偶联”为中文检索词检索万方和中国知网数据库,最终纳入88篇文献进行综述。结果与结论:①去铁胺能招募干细胞并调节干细胞功能,激活相关信号通路提高细胞的低氧适应能力,发挥抗炎抗氧化特性改善局部炎性环境,并通过偶联成骨-成血管及抑制骨吸收来促进骨再生。②相较于传统骨组织工程中加载的生长因子或多肽,去铁胺作为小分子药物具有独特的优势,同时也存在毒性反应及应用局限,因此优化载药形式及剂量是必要的。③去铁胺独特的成血管-成骨偶联能力,在不同类型的骨损伤如骨折、骨坏死、牵张成骨、骨移植、口腔相关成骨及骨缺损中,因对骨愈合过程中血管生成的加强而更能适应和解决复杂多变的临床情况及个体差异下造成的骨修复困难;但同时也需要对去铁胺的应用方式及安全剂量加以对比和优化,利于其应用范围的扩大及临床价值的提升。
