共查询到20条相似文献,搜索用时 15 毫秒
1.
Chrisoula A. Toupadakis Alice Wong Damian C. Genetos Dai‐Jung Chung Deepa Murugesh Matthew J. Anderson Gabriela G. Loots Blaine A. Christiansen Amy S. Kapatkin Clare E. Yellowley 《Journal of orthopaedic research》2012,30(11):1853-1859
Fracture healing involves rapid stem and progenitor cell migration, homing, and differentiation. SDF‐1 (CXCL12) is considered a master regulator of CXCR4‐positive stem and progenitor cell trafficking to sites of ischemic (hypoxic) injury and regulates their subsequent differentiation into mature reparative cells. In this study, we investigated the role of SDF‐1/CXCR4 signaling in fracture healing where vascular disruption results in hypoxia and SDF‐1 expression. Mice were injected with AMD3100, a CXCR4 antagonist, or vehicle twice daily until euthanasia with the intent to impair stem cell homing to the fracture site and/or their differentiation. Fracture healing was evaluated using micro‐computed tomography, histology, quantitative PCR, and mechanical testing. AMD3100 administration resulted in a significantly reduced hyaline cartilage volume (day 14), callus volume (day 42) and mineralized bone volume (day 42) and reduced expression of genes associated with endochondral ossification including collagen Type 1 alpha 1, collagen Type 2 alpha 1, vascular endothelial growth factor, Annexin A5, nitric oxide synthase 2, and mechanistic target of rapamycin. Our data suggest that the SDF‐1/CXCR4 signaling plays a central role in bone healing possibly by regulating the recruitment and/or differentiation of stem and progenitor cells. © 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 30:1853–1859, 2012 相似文献
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Philipp Leucht Sara Temiyasathit Ashley Russell Juan F. Arguello Christopher R. Jacobs Jill A. Helms Alesha B. Castillo 《Journal of orthopaedic research》2013,31(11):1828-1838
Mechanical loading is a key anabolic regulator of bone mass. Stromal cell‐derived factor‐1 (SDF‐1) is a stem cell homing factor that is important in hematopoiesis, angiogenesis, and fracture healing, though its involvement in skeletal mechanoadaptation is virtually unknown. The objective of this study was to characterize skeletal expression patterns of SDF‐1 and CXCR4, the receptor for SDF‐1, and to determine the role of SDF‐1 signaling in load‐induced periosteal bone formation. Sixteen‐week‐old C57BL/6 mice were treated with PBS or AMD3100, an antagonist against CXCR4, and exposed to in vivo ulnar loading (2.8 N peak‐to‐peak, 2 Hz, 120 cycles). SDF‐1 was expressed in cortical and trabecular osteocytes and marrow cells, and CXCR4 was primarily expressed in marrow cells. SDF‐1 and CXCR4 expression was enhanced in response to mechanical stimulation. The CXCR4 receptor antagonist AMD3100 significantly attenuated load‐induced bone formation and led to smaller adaptive changes in cortical geometric properties as determined by histomorphometric analysis. Our data suggest that SDF‐1/CXCR4 signaling plays a critical role in skeletal mechanoadaptation, and may represent a unique therapeutic target for prevention and treatment of age‐related and disuse bone loss. © 2013 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 31:1828–1838, 2013 相似文献
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Macrophage Migration Inhibitory Factor (MIF) Supports Homing of Osteoclast Precursors to Peripheral Osteolytic Lesions 下载免费PDF全文
Alexandru Movila Takenobu Ishii Abdullah Albassam Wichaya Wisitrasameewong Mohammed Howait Tsuguno Yamaguchi Montserrat Ruiz‐Torruella Laila Bahammam Kazuaki Nishimura Thomas Van Dyke Toshihisa Kawai 《Journal of bone and mineral research》2016,31(9):1688-1700
By binding to its chemokine receptor CXCR4 on osteoclast precursor cells (OCPs), it is well known that stromal cell‐derived factor‐1 (SDF‐1) promotes the chemotactic recruitment of circulating OCPs to the homeostatic bone remodeling site. However, the engagement of circulating OCPs in pathogenic bone resorption remains to be elucidated. The present study investigated a possible chemoattractant role of macrophage migration inhibitory factor (MIF), another ligand for C‐X‐C chemokine receptor type 4 (CXCR4), in the recruitment of circulating OCPs to the bone lytic lesion. To accomplish this, we used Csf1r‐eGFP‐knock‐in (KI) mice to establish an animal model of polymethylmethacrylate (PMMA) particle‐induced calvarial osteolysis. In the circulating Csf1r‐eGFP+ cells of healthy Csf1r‐eGFP‐KI mice, Csf1r+/CD11b+ cells showed a greater degree of RANKL‐induced osteoclastogenesis compared to a subset of Csf1r+/RANK+ cells in vitro. Therefore, Csf1r‐eGFP+/CD11b+ cells were targeted as functionally relevant OCPs in the present study. Although expression of the two cognate receptors for MIF, CXCR2 and CXCR4, was elevated on Csf1r+/CD11b+ cells, transmigration of OCPs toward recombinant MIF in vitro was facilitated by ligation with CXCR4, but not CXCR2. Meanwhile, the level of PMMA‐induced bone resorption in calvaria was markedly greater in wild‐type (WT) mice compared to that detected in MIF‐knockout (KO) mice. Interestingly, in contrast to the elevated MIF, diminished SDF‐1 was detected in a particle‐induced bone lytic lesion of WT mice in conjunction with an increased number of infiltrating CXCR4+ OCPs. However, such diminished SDF‐1 was not found in the PMMA‐injected calvaria of MIF‐KO mice. Furthermore, stimulation of osteoblasts with MIF in vitro suppressed their production of SDF‐1, suggesting that MIF can downmodulate SDF‐1 production in bone tissue. Systemically administered anti‐MIF neutralizing monoclonal antibody (mAb) inhibited the homing of CXCR4+ OCPs, as well as bone resorption, in the PMMA‐injected calvaria, while increasing locally produced SDF‐1. Collectively, these data suggest that locally produced MIF in the inflammatory bone lytic site is engaged in the chemoattraction of circulating CXCR4+ OCPs. © 2016 American Society for Bone and Mineral Research. 相似文献
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Daniel Toben Ireen Schroeder Thaqif El Khassawna Manav Mehta Jan‐Erik Hoffmann Jan‐Tilmann Frisch Hanna Schell Jasmin Lienau Alessandro Serra Andreas Radbruch Georg N Duda 《Journal of bone and mineral research》2011,26(1):113-124
Fracture healing is a unique biologic process starting with an initial inflammatory response. As in other regenerative processes, bone and the immune system interact closely during fracture healing. This project was aimed at further elucidating how the host immune system participates in fracture healing. A standard closed femoral fracture was created in wild‐type (WT) and recombination activating gene 1 knockout (RAG1?/?) mice lacking the adaptive immune system. Healing was investigated using micro–computed tomography (µCT), biomechanical testing, and histologic and mRNA expression analyses. Biomechanical testing demonstrated a significantly higher torsional moment on days 14 and 21 in the RAG1?/? mice compared to the WT group. µCT evaluation of RAG1?/? specimens showed earlier mineralization and remodeling. Histologically, endochondral ossification and remodeling were accelerated in the RAG1?/? compared with the WT mice. Histomorphometric analysis on day 7 showed a significantly higher fraction of bone and a significantly lower fraction of cartilage in the callus of the RAG1?/? mice than in the WT mice. Endochondral ossification was accelerated in the RAG1?/? mice. Lymphocytes were present during the physiologic repair process, with high numbers in the hematoma on day 3 and during formation of the hard callus on day 14 in the WT mice. Expression of inflammatory cytokines was reduced in the RAG1?/? mice. In contrast, expression of anti‐inflammatory interleukin 10 (IL‐10) was strongly upregulated in RAG1?/? mice, indicating protective effects. This study revealed an unexpected phenotype of enhanced fracture healing in RAG1?/? mice, suggesting detrimental functions of lymphocytes on fracture healing. The shift from proinflammatory to anti‐inflammatory cytokines suggests that immunomodulatory intervention strategies that maximise the regenerative and minimize the destructive effects of inflammation may lead to enhanced fracture repair. © 2011 American Society for Bone and Mineral Research. 相似文献
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Kevin R. O'Neill Christopher M. Stutz Nicholas A. Mignemi Heather Cole Matthew R. Murry Jeffry S. Nyman Heidi Hamm Jonathan G. Schoenecker 《Journal of orthopaedic research》2012,30(8):1271-1276
Protease‐activated receptor‐2 (PAR‐2) provides an important link between extracellular proteases and the cellular initiation of inflammatory responses. The effect of PAR‐2 on fracture healing is unknown. This study investigates the in vivo effect of PAR‐2 deletion on fracture healing by assessing differences between wild‐type (PAR‐2+/+) and knock‐out (PAR‐2?/?) mice. Unilateral mid‐shaft femur fractures were created in 34 PAR‐2+/+ and 28 PAR‐2?/? mice after intramedullary fixation. Histologic assessments were made at 1, 2, and 4 weeks post‐fracture (wpf), and radiographic (plain radiographs, micro‐computed tomography (µCT)) and biomechanical (torsion testing) assessments were made at 7 and 10 wpf. Both the fractured and un‐fractured contralateral femur specimens were evaluated. Polar moment of inertia (pMOI), tissue mineral density (TMD), bone volume fraction (BV/TV) were determined from µCT images, and callus diameter was determined from plain radiographs. Statistically significant differences in callus morphology as assessed by µCT were found between PAR‐2?/? and PAR‐2+/+ mice at both 7 and 10 wpf. However, no significant histologic, plain radiographic, or biomechanical differences were found between the genotypes. The loss of PAR‐2 was found to alter callus morphology as assessed by µCT but was not found to otherwise effect fracture healing in young mice. © 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 30:1271–1276, 2012 相似文献
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Hypochlorhydria‐induced calcium malabsorption does not affect fracture healing but increases post‐traumatic bone loss in the intact skeleton 下载免费PDF全文
Melanie Haffner‐Luntzer Aline Heilmann Verena Heidler Astrid Liedert Thorsten Schinke Michael Amling Timur Alexander Yorgan Annika vom Scheidt Anita Ignatius 《Journal of orthopaedic research》2016,34(11):1914-1921
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NAD(P)H‐quinone oxidoreductase 1 silencing aggravates hormone‐induced prostatic hyperplasia in mice 下载免费PDF全文
NAD(P)H‐quinone oxidoreductase 1 (NQO1) is a highly inducible flavoprotein known to involve in various cellular defence mechanisms. In this study, we explored whether NQO1 deletion affects hormone‐induced prostatic hyperplasia. Testosterone propionate (3 mg/kg, IP) was injected into wild‐type (WT) and NOQ1 knockout C57BL/6 mice (NQO1?/?) for 14 consecutive days, and the samples were collected for biological and histochemical studies. The testosterone‐treated NQO1?/? showed about 140% higher prostate weight than the testosterone‐treated WT, with enhanced connective tissue and hyperplastic glands formations. However, increased dihydrotestosterone level after testosterone treatment was not significantly different between the WT and NQO1?/?. In contrast, the enhanced nuclear expression of proliferating cell nuclear antigen in NQO1?/? prostate confirmed aggravated prostatic hyperplasia in NQO1?/?. Moreover, the expression of heat shock protein (HSP) 90‐α was markedly increased in the NQO1?/?, and this was supported by increased testosterone‐induced nuclear androgen receptor expression in NQO1‐silenced LNCaP cells. Testosterone‐induced prostate‐specific antigen expression was not reversed in NOQ1‐silenced cells after finasteride treatment. Although the exact role of NQO1 in prostatic hyperplasia remains unclear, the hyperplasia exacerbation due to NQO1 deletion might be independent of type 2 5α‐reductase and might be related to enhanced androgen receptor affinity due to enhanced HSP90‐α expression. 相似文献
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Zhijie Dai Sookja K Chung Dengshun Miao Kam S Lau Alfred WH Chan Annie WC Kung 《Journal of bone and mineral research》2011,26(3):582-590
myo‐Inositol (MI) plays an essential role in several important processes of cell physiology, is involved in the neural system, and provides an effective treatment for some psychiatric disorders. Its role in osteogenesis and bone formation nonetheless is unclear. Sodium/MI cotransporter 1 (SMIT1, the major cotransporter of MI) knockout (SMIT1?/?) mice with markedly reduced tissue MI levels were used to characterize the essential roles of MI and SMIT1 in osteogenesis. SMIT1?/? embryos had a dramatic delay in prenatal mineralization and died soon after birth owing to respiratory failure, but this could be rescued by maternal MI supplementation. The rescued SMIT1?/? mice had shorter limbs, decreased bone density, and abnormal bone architecture in adulthood. Deletion of SMIT1 resulted in retarded postnatal osteoblastic differentiation and bone formation in vivo and in vitro. Continuous MI supplementation partially restored the abnormal bone phenotypes in adult SMIT1?/? mice and strengthened bone structure in SMIT1+/+ mice. Although MI content was much lower in SMIT1?/? mesenchymal cells (MSCs), the I(1,4,5)P3 signaling pathway was excluded as the means by which SMIT1 and MI affected osteogenesis. PCR expression array revealed Fgf4, leptin, Sele, Selp, and Nos2 as novel target genes of SMIT1 and MI. SMIT1 was constitutively expressed in multipotential C3H10T1/2 and preosteoblastic MC3T3‐E1 cells and could be upregulated during bone morphogenetic protein 2 (BMP‐2)–induced osteogenesis. Collectively, this study demonstrated that deficiency in SMIT1 and MI has a detrimental impact on prenatal skeletal development and postnatal bone remodeling and confirmed their essential roles in osteogenesis, bone formation, and bone mineral density (BMD) determination. © 2011 American Society for Bone and Mineral Research. 相似文献
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Lin Chen MD PhD Sridevi Nagaraja PhD Jian Zhou BS Yan Zhao BS David Fine BS Alexander Y. Mitrophanov PhD Jaques Reifman PhD Luisa A. DiPietro DDS PhD 《Wound repair and regeneration》2017,25(3):366-376
Mac‐1 (CD11b/CD18) is a macrophage receptor that plays several critical roles in macrophage recruitment and activation. Because macrophages are essential for proper wound healing, the impact of Mac‐1 deficiency on wound healing is of significant interest. Prior studies have shown that Mac‐1?/? mice exhibit deficits in healing, including delayed wound closure in scalp and ear wounds. This study examined whether Mac‐1 deficiency influences wound healing in small excisional and incisional skin wounds. Three millimeter diameter full thickness excisional wounds and incisional wounds were prepared on the dorsal skin of Mac‐1 deficient (Mac‐1?/?) and wild type (WT) mice, and wound healing outcomes were examined. Mac‐1 deficient mice exhibited a normal rate of wound closure, generally normal levels of total collagen, and nearly normal synthesis and distribution of collagens I and III. In incisional wounds, wound breaking strength was similar for Mac‐1?/? and WT mice. Wounds of Mac‐1 deficient mice displayed normal total macrophage content, although macrophage phenotype markers were skewed as compared to WT. Interestingly, amounts of TGF‐β1 and its downstream signaling molecules, SMAD2 and SMAD3, were significantly decreased in the wounds of Mac‐1 deficient mice compared to WT. The results suggest that Mac‐1 deficiency has little impact on the healing of small excisional and incisional wounds. Moreover, the findings demonstrate that the effect of single genetic deficiencies on wound healing may markedly differ among wound models. These conclusions have implications for the interpretation of the many prior studies that utilize a single model system to examine wound healing outcomes in genetically deficient mice. 相似文献
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Paulo Henrique Luiz de Freitas Minqi Li Tadashi Ninomiya Midori Nakamura Sobhan Ubaidus Kimimitsu Oda Nobuyuki Udagawa Takeyasu Maeda Ritsuo Takagi Norio Amizuka DDS PhD 《Journal of bone and mineral research》2009,24(9):1586-1597
This study aimed to investigate the behavior and ultrastructure of osteoblastic cells after intermittent PTH treatment and attempted to elucidate the role of osteoclasts on the mediation of PTH‐driven bone anabolism. After administering PTH intermittently to wildtype and c‐fos?/? mice, immunohistochemical, histomorphometrical, ultrastructural, and statistical examinations were performed. Structural and kinetic parameters related to bone formation were increased in PTH‐treated wildtype mice, whereas in the osteoclast‐deficient c‐fos?/? mice, there were no significant differences between groups. In wildtype and knockout mice, PTH administration led to significant increases in the number of cells double‐positive for alkaline phosphatase and BrdU, suggesting active pre‐osteoblastic proliferation. Ultrastructural examinations showed two major pre‐osteoblastic subtypes: one rich in endoplasmic reticulum (ER), the hypER cell, and other with fewer and dispersed ER, the misER cell. The latter constituted the most abundant preosteoblastic phenotype after PTH administration in the wildtype mice. In c‐fos?/? mice, misER cells were present on the bone surfaces but did not seem to be actively producing bone matrix. Several misER cells were shown to be positive for EphB4 and were eventually seen rather close to osteoclasts in the PTH‐administered wildtype mice. We concluded that the absence of osteoclasts in c‐fos?/? mice might hinder PTH‐driven bone anabolism and that osteoclastic presence may be necessary for full osteoblastic differentiation and enhanced bone formation seen after intermittent PTH administration. 相似文献
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Effects of knockout of the receptor for advanced glycation end‐products on bone mineral density and synovitis in mice with intra‐articular fractures 下载免费PDF全文
Dongrim Seol Yuki Tochigi Ashley M. Bogner Ino Song Douglas C. Fredericks Gail L. Kurriger Sonja M. Smith Jessica E. Goetz Joseph A. Buckwalter James A. Martin 《Journal of orthopaedic research》2018,36(9):2439-2449
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Jeffry S Nyman Conor C Lynch Daniel S Perrien Sophie Thiolloy Elizabeth C O'Quinn Chetan A Patil Xiaohong Bi George M Pharr Anita Mahadevan‐Jansen Gregory R Mundy 《Journal of bone and mineral research》2011,26(6):1252-1260
Matrix metalloproteinases (MMPs) are capable of processing certain components of bone tissue, including type 1 collagen, a determinant of the biomechanical properties of bone tissue, and they are expressed by osteoclasts and osteoblasts. Therefore, we posit that MMP activity can affect the ability of bone to resist fracture. To explore this possibility, we determined the architectural, compositional, and biomechanical properties of bones from wild‐type (WT), Mmp2?/?, and Mmp9?/? female mice at 16 weeks of age. MMP‐2 and MMP‐9 have similar substrates but are expressed primarily by osteoblasts and osteoclasts, respectively. Analysis of the trabecular compartment of the tibia metaphysis by micro–computed tomography (µCT) revealed that these MMPs influence trabecular architecture, not volume. Interestingly, the loss of MMP‐9 improved the connectivity density of the trabeculae, whereas the loss of MMP‐2 reduced this parameter. Similar differential effects in architecture were observed in the L5 vertebra, but bone volume fraction was lower for both Mmp2?/? and Mmp9?/? mice than for WT mice. The mineralization density and mineral‐to‐collagen ratio, as determined by µCT and Raman microspectroscopy, were lower in the Mmp2?/? bones than in WT control bones. Whole‐bone strength, as determined by three‐point bending or compression testing, and tissue‐level modulus and hardness, as determined by nanoindentation, were less for Mmp2?/? than for WT bones. In contrast, the Mmp9?/? femurs were less tough with lower postyield deflection (more brittle) than the WT femurs. Taken together, this information reveals that MMPs play a complex role in maintaining bone integrity, with the cell type that expresses the MMP likely being a contributing factor to how the enzyme affects bone quality. © 2011 American Society for Bone and Mineral Research. 相似文献
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A. K. Sharma D. J. LaPar M. L. Stone Y. Zhao I. L. Kron V. E. Laubach 《American journal of transplantation》2013,13(9):2255-2267
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Daniela M. Sousa Michelle M. McDonald Kathy Mikulec Lauren Peacock Herbert Herzog Meriem Lamghari David G. Little Paul A. Baldock 《Journal of orthopaedic research》2013,31(10):1570-1578
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K. Yamaura O. Boenisch T. Watanabe T. Ueno V. Vanguri J. Yang K. Tanaka I. Guleria J. Borst Y. Zhai J. W. Kupiec‐Weglinski N. Najafian 《American journal of transplantation》2010,10(5):1210-1220
CD8+ memory T cells endanger allograft survival by causing acute and chronic rejection and prevent tolerance induction. We explored the role of CD27:CD70 T‐cell costimulatory pathway in alloreactive CD8+/CD4+ T‐cell activation. CD27‐deficient (CD27?/?) and wild‐type (WT) B6 mice rejected BALB/c cardiac allografts at similar tempo, with or without depletion of CD4+ or CD8+ T cells, suggesting that CD27 is not essential during primary T‐cell alloimmune responses. To dissect the role of CD27 in primed effector and memory alloreactive T cells, CD27?/? or WT mice were challenged with BALB/c hearts either 10 or 40 days after sensitization with donor‐type skin grafts. Compared to WT controls, allograft survival was prolonged in day 40‐ but not day 10‐sensitized CD27?/? recipients. Improved allograft survival was accompanied by diminished secondary responsiveness of memory CD8+ T cells, which resulted from deficiency in memory formation rather than their lack of secondary expansion. Chronic allograft vasculopathy and fibrosis were diminished in CD27?/? recipients of class I‐ but not class II‐mismatched hearts as compared to WT controls. These data establish a novel role for CD27 as an important costimulatory molecule for alloreactive CD8+ memory T cells in acute and chronic allograft rejection. 相似文献
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CXCR4 antagonist delivery on decellularized skin scaffold facilitates impaired wound healing in diabetic mice by increasing expression of SDF‐1 and enhancing migration of CXCR4‐positive cells 下载免费PDF全文
Hao Liu MS Hanping Liu PhD Xiaoyuan Deng PhD Maosheng Chen MS Xue Han MS Wenxia Yan MS Ning Wang MS 《Wound repair and regeneration》2017,25(4):652-664
C‐X‐C chemokine receptor type 4 (CXCR4) is an alpha‐chemokine receptor specific for stromal cell‐derived factor 1 (SDF‐1 also called CXCL12). The antagonist of CXCR4 can mobilize CD34+ cells and hematopoietic stem cells from bone marrow within several hours, and it has an efficacy on diabetes ulcer through acting on the SDF‐1/CXCR4 axis. In this study, we investigated for the first time whether the antagonist of CXCR4 (Plerixafor/AMD3100) delivered on acellular dermal matrix (ADM) may accelerate diabetes‐impaired wound healing. ADM scaffolds were fabricated from nondiabetic mouse skin through decellularization processing and incorporated with AMD3100 to construct ADM‐AMD3100 scaffold. Full‐thickness cutaneous wound in streptozotocin (STZ)‐induced diabetic mice were treated with ADM, AMD3100, or ADM‐AMD3100. 21 days after treatment, wound closure in ADM‐AMD3100‐treated mice was more complete than ADM group and AMD3100 group, and it was accompanied by thicker collagen formation. Correspondingly, diabetic mice treated with ADM‐AMD3100 demonstrated prominent neovascularization (higher capillary density and vascular smooth muscle actin), which were accompanied by up‐regulated mRNA levels of SDF‐1 and enhanced migration of CXCR4 in the granulation tissue. Our results demonstrate that ADM scaffold provide perfect niche for loading AMD3100 and ADM‐AMD3100 is a promising method for diabetic wound healing mainly by increasing expression of SDF‐1 and enhancing migration of CXCR4‐positive cells. 相似文献