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Yi Zhang - One of the best experts on this subject based on the ideXlab platform.
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TRPV1 deletion impaired fracture healing and inhibited osteoclast and osteoblast differentiation
Scientific reports, 2017Co-Authors: Meng Liu, E. Xiao, Lu Zhao, Ting Zhang, Hua-qian Yang, Yi ZhangAbstract:Fracture healing, in which osteoclasts and osteoblasts play important roles, has drawn much clinical attention. Osteoclast deficiency or decreased osteoblast activity will impair fracture healing. TRPV1 is a member of the Ca2+ permeable cation channel subfamily, and pharmacological inhibition of TRPV1 prevents ovariectomy-induced bone loss, which makes TRPV1 a potential target for osteoporosis. However, whether long term TRPV1 inhibition or TRPV1 deletion will affect the fracture healing process is unclear. In this study, we found that the wild-type mice showed a well-remodeled fracture Callus, whereas TRPV1 knockout mice still had an obvious fracture gap with unresorbed Soft-Callus 4 weeks post-fracture. The number of osteoclasts was reduced in the TRPV1 knockout fracture Callus, and osteoclast formation and resorption activity were also impaired in vitro. TRPV1 deletion decreased the calcium oscillation frequency and peak cytoplasmic concentration in osteoclast precursors, subsequently reducing the expression and nuclear translocation of NFATc1 and downregulating DC-stamp, cathepsin K, and ATP6V. In addition, TRPV1 deletion caused reduced mRNA and protein expression of Runx2 and ALP in bone marrow stromal cells (BMSCs) and reduced calcium deposition in vitro. Our results suggest that TRPV1 deletion impairs fracture healing, and inhibited osteoclastogenesis and osteogenesis.
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TRPV1 deletion impaired fracture healing and inhibited osteoclast and osteoblast differentiation
SCIENTIFIC REPORTS, 2017Co-Authors: He Lin-hai, Lu Zhao, Liu Meng, He Yang, Xiao E., Zhang Ting, Yang Hua-qian, Yi ZhangAbstract:Fracture healing, in which osteoclasts and osteoblasts play important roles, has drawn much clinical attention. Osteoclast deficiency or decreased osteoblast activity will impair fracture healing. TRPV1 is a member of the Ca2+ permeable cation channel subfamily, and pharmacological inhibition of TRPV1 prevents ovariectomy-induced bone loss, which makes TRPV1 a potential target for osteoporosis. However, whether long term TRPV1 inhibition or TRPV1 deletion will affect the fracture healing process is unclear. In this study, we found that the wild-type mice showed a well-remodeled fracture Callus, whereas TRPV1 knockout mice still had an obvious fracture gap with unresorbed Soft-Callus 4 weeks post-fracture. The number of osteoclasts was reduced in the TRPV1 knockout fracture Callus, and osteoclast formation and resorption activity were also impaired in vitro. TRPV1 deletion decreased the calcium oscillation frequency and peak cytoplasmic concentration in osteoclast precursors, subsequently reducing the expression and nuclear translocation of NFATc1 and downregulating DC-stamp, cathepsin K, and ATP6V. In addition, TRPV1 deletion caused reduced mRNA and protein expression of Runx2 and ALP in bone marrow stromal cells (BMSCs) and reduced calcium deposition in vitro. Our results suggest that TRPV1 deletion impairs fracture healing, and inhibited osteoclastogenesis and osteogenesis.National Natural Science Foundation of China [81371117]; Beijing Natural Science Foundation [7152155]SCI(E)ARTICLE
Georg N. Duda - One of the best experts on this subject based on the ideXlab platform.
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A4.01 T cells are critical regulators of Soft Callus mineralization and normal deposition of collagen I during bone repair
Annals of the Rheumatic Diseases, 2016Co-Authors: Alessandro Serra, Hanna Schell, T. El Khassawna, Ansgar Petersen, Claudia Schlundt, Ireen Könnecke, H.-d. Volk, Andreas Radbruch, Katharina Schmidt-bleek, Georg N. DudaAbstract:Background and objectives The critical interdependency between the skeletal and immune system has been demonstrated for the fracture healing process. However, the current state of the art is contradictory. On one hand, lymphopenic mice display alleged better healing after injury. On the other hand, several studies attribute either a positive or negative role to T and B cells in bone biology, autoimmunity and fracture healing. The objective of this study is to elucidate the specific role of T and B cells in fracture repair toward early Callus mineralization, bone quality, migration of osteoblast precursors and Collagen I deposition. Materials and methods Unilateral closed femoral fractures were produced in RAG1-/-, TCR βδ chain -/-, JHT -/- and C57BL/6 wild-type mice. Bone healing was assessed by histology, biomechanical testing and fluorochrome deposition. Deposition and structural properties of CollagenI were studied by second harmonic and confocal microscopy. Callus gene expression was determined by microarray analysis. Osteoblast precursors, T and B cell migration in the Callus were visualised by confocal microscopy. Results Fractured bones of RAG -/- mice mineralized faster, but were much less capable to withstand deformation. Similarly, RAG -/- mice deposited bone quicker during the earliest phases of healing, whereas at later stages underperformed relative to controls. RAG -/- mice also failed to deposit a cross gap layer of Collagen I which correlated with diminished immigration of osteoblast precursors in the peripheral Callus. The remaining network of Collagen I fibres in these mice was found to be highly disordered. Interestingly, no alteration in osteoblast precursor migration was observed when only either T or B cells were absent. However, Collagen I deposition was strongly impaired in T cell but not in B cell deficient mice. There, Collagen I fibres failed to organise across the gap in the peripheral Callus displaying a highly disordered pattern of deposition. Conclusions Overall our data show that lack of an adaptive immune system does not lead to better, but rather deregulated and suboptimal bone healing. These features were recapitulated in mice that specifically lacked T and not B cells.
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T and B cells participate in bone repair by infiltrating the fracture Callus in a two-wave fashion.
Bone, 2014Co-Authors: Ireen Könnecke, Hanna Schell, Alessandro Serra, Claudia Schlundt, Andreas Radbruch, Thaqif El Khassawna, Anja E. Hauser, Agnes Ellinghaus, Hans-dieter Volk, Georg N. DudaAbstract:Fracture healing is a regenerative process in which bone is restored without scar tissue formation. The healing cascade initiates with a cycle of inflammation, cell migration, proliferation and differentiation. Immune cells invade the fracture site immediately upon bone damage and contribute to the initial phase of the healing process by recruiting accessory cells to the injury site. However, little is known about the role of the immune system in the later stages of fracture repair, in particular, whether lymphocytes participate in Soft and hard Callus formation. In order to answer this question, we analyzed femoral fracture healing in mice by confocal microscopy. Surprisingly, after the initial inflammatory phase, when Soft Callus developed, T and B cells withdrew from the fracture site and were detectable predominantly at the femoral neck and knee. Thereafter lymphocytes massively infiltrated the Callus region (around day 14 after injury), during Callus mineralization. Interestingly, lymphocytes were not found within cartilaginous areas of the Callus but only nearby the newly forming bone. During healing B cell numbers seemed to exceed those of T cells and B cells progressively underwent effector maturation. Both, osteoblasts and osteoclasts were found to have direct cell-cell contact with lymphocytes, strongly suggesting a regulatory role of the immune cells specifically in the later stages of fracture healing.
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IN VIVO TRACKING OF SEGMENTAL BONE DEFECT HEALING REVEALS THAT Callus PATTERNING IS RELATED TO EARLY MECHANICAL STIMULI
European cells & materials, 2012Co-Authors: Manav Mehta, Jasmin Lienau, Sara Checa, Dietmar W. Hutmacher, Georg N. DudaAbstract:This study addresses the hypothesis that Callus formation, patterning, and mineralisation are impaired during the early phase of critical sized bone defect healing, and may relate to inter-fragmentary tissue strains within the bone defect area. Twenty four 12 week old Sprague Dawley rats were used for this study. They were divided into two groups defined by the femur bone defect size: (i) 1 mm resulting in normal healing (NH), and (ii) a large sized 5 mm defect resulting in critical healing (CH). Callus formation, patterning, and mineralisation kinetics in both groups were examined in the periosteal and osteotomy gap regions using a novel longitudinal study setup. Finite element analyses on µCT generated tomograms were used to determine inter-fragmentary tissue strain patterns and compared to Callus formation and patterning over the course of time. Using a novel longitudinal study technique with µCT, in vivo tracking and computer simulation approaches, this study demonstrates that: (i) periosteal bone formation and patterning are significantly influenced by bone defect size as early as 2 weeks; (ii) osteotomy gap Callus formation and patterning are influenced by bone defect size, and adapt towards a non-union in critical cases by deviating into a medullary formation route as early as 2 weeks after osteotomy; (iii) the new bone formation in the osteotomy gap enclosing the medullary cavity in the CH group is highly mineralised; (iv) inter-fragmentary strain patterns predicted during the very early Soft Callus tissue phase (less than 2 weeks) are concurrent with Callus formation and patterning at later stages. In conclusion, bone defect size influences early onset of critical healing patterns.
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Digital image correlation: a technique for determining local mechanical conditions within early bone Callus.
Medical engineering & physics, 2006Co-Authors: Mark S. Thompson, Hanna Schell, Jasmin Lienau, Georg N. DudaAbstract:Abstract Local mechanical conditions are known to play a role during the regeneration of musculoskeletal tissues, and histomorphometrical investigations of the time course of healing have enabled specific conclusions regarding the mechanosensitivity of tissue differentiation. However, the mechanism for this influence is not clearly understood. In order to extend this analysis, it is essential to link local histological understanding with direct characterisation of the local mechanical environment. Digital image correlation (DIC) is a computer-based image analysis technique that enables the non-contact measurement of strains on material surfaces and is finding application in many areas of biomechanics. Here we report a DIC technique to investigate the local distribution of mechanical strain within regenerating Soft tissue sections. We provide exemplary data from analysis of a section of sheep bone Callus. An assessment of displacement measurement accuracy gave an RMS error of 4.2 μm, corresponding to an estimated strain error of 1.4%. The sections showed concentrations of up to four times the applied strain and comparison of the strain patterns with histological analysis confirmed that these concentrations reflected boundaries between hard and Soft Callus.
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Do serological tissue turnover markers represent Callus formation during fracture healing
Bone, 2005Co-Authors: P. Seebeck, H.j. Bail, C. Exner, H. Schell, R. Michel, H. Amthauer, H. Bragulla, Georg N. DudaAbstract:Abstract Serological parameters of bone and fibrous tissue turnover were demonstrated to monitor the course of fracture healing. The aim of this study was to evaluate the correlation between the serological parameter levels during fracture healing and Callus development in a standardised ovine model of fracture healing. Two years old female sheep received a standardised 3 mm tibial bone defect stabilised by an external fixator. The serological levels of the C-terminal propeptide of procollagen type I (PICP), bone specific alkaline phosphatase (bALP), total alkaline phosphatase (tALP), osteocalcin, tartrate-resistant acid phosphatase (TRAP), calcium, phosphate and the N-terminal peptide of procollagen type III (PIIINP) were observed over a 9-week healing period. The course of fracture healing was monitored radiographically, and the Callus composition was evaluated histologically at 2, 3, 6 and 9 weeks post-surgery. The serological results were compared with an untreated control group. Additionally, the maximum values during healing were compared with juvenile values to gauge the level of the serological response. The histological and radiographical results demonstrated Callus formation without complications. All serological parameters showed broad inter-individual variations, and the response to the standardised fracture scenario was strongly individual. Maximum values during fracture healing did not reach the juvenile levels. The fractured as well as the control animals showed significant changes in the parameter levels. No correlations were observed between the histological course of healing and the course of bone formation markers whilst the TRAP level was reduced during bony Callus formation. The PIIINP level increased when the amount of Soft Callus tissue decreased during healing. The observed bone formation markers were not suitable as general markers to detect the course of fracture healing, whilst PIIINP was able to reflect Soft Callus degradation.
Andrew Harrison - One of the best experts on this subject based on the ideXlab platform.
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Low intensity pulsed ultrasound for fracture healing: a review of the clinical evidence and the associated biological mechanism of action.
Ultrasonics, 2008Co-Authors: Neill M. Pounder, Andrew HarrisonAbstract:Abstract Low intensity pulsed ultrasound is used in the clinical treatment of fractures and other osseous defects. Level I clinical studies demonstrate the ability of a specific ultrasound signal (1.5 MHz ultrasound pulsed at 1 kHz, 20% duty cycle, 30 mW/cm 2 intensity (SATA)) to accelerate the healing time in fresh tibia, radius and scaphoid fractures by up to 40%. Additionally, the same ultrasound signal has been shown to be effective at resolving all types of nonunions of all ages, following a wide range of fracture types and primary fracture management techniques. Recently, significant efforts have resulted in a more comprehensive understanding of the biological mechanism of action that produces the documented clinical outcomes. Low intensity pulsed ultrasound has been demonstrated to accelerate in vivo all stages of the fracture repair process (inflammation, Soft Callus formation, hard Callus formation). In particular, accelerated mineralisation has been demonstrated in vitro with increases in osteocalcin, alkaline phosphatase, VEGF and MMP-13 expression. Integrins, a family of mechanoreceptors present on a wide range of cells involved in the fracture healing process, have been shown to be activated by the ultrasound signal. Downstream of the integrin activation, focal adhesions occur on the surface of cells with the activation of multiple signalling pathways, including the ERK, NF-κβ, and PI3 kinase pathways. These pathways have been directly linked to the production of COX-2 and prostaglandin, which are key to the processes of mineralisation and endochondral ossification in fracture healing.
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Pulsed low intensity ultrasound enhances mineralisation in preosteoblast cells.
Ultrasound in medicine & biology, 2007Co-Authors: Jenny Unsworth, Saira Kaneez, Sue Harris, Jonathan Nicholas Ridgway, Steven Fenwick, David Chenery, Andrew HarrisonAbstract:Abstract Pulsed low intensity ultrasound has been shown to be highly efficacious in the treatment of nonunion fractures and in the acceleration of fresh fracture healing. MC3T3-E1 subclone 14 cells were cultured for up to 25 days either with or without a daily treatment with low intensity pulsed ultrasound. It was determined that, on day 10 there was a dramatic increase in alkaline phosphatase and MMP-13 mRNA levels detected in ultrasound-treated cultures compared with untreated controls. The activity of alkaline phosphatase was significantly increased at days 6, 8 and 10. On day 10, the amount of mineralisation within cultures, assessed using alizarin red staining, was significantly increased in ultrasound-treated cultures compared with untreated controls. These results suggest that one of the mechanisms that low intensity pulsed ultrasound has on fracture repair is to enhance the process of endochondral ossification where the Soft Callus is converted to mineralised hard Callus. (E-mail: andrew.harrison@smith-nephew.com )
Lu Zhao - One of the best experts on this subject based on the ideXlab platform.
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TRPV1 deletion impaired fracture healing and inhibited osteoclast and osteoblast differentiation
Scientific reports, 2017Co-Authors: Meng Liu, E. Xiao, Lu Zhao, Ting Zhang, Hua-qian Yang, Yi ZhangAbstract:Fracture healing, in which osteoclasts and osteoblasts play important roles, has drawn much clinical attention. Osteoclast deficiency or decreased osteoblast activity will impair fracture healing. TRPV1 is a member of the Ca2+ permeable cation channel subfamily, and pharmacological inhibition of TRPV1 prevents ovariectomy-induced bone loss, which makes TRPV1 a potential target for osteoporosis. However, whether long term TRPV1 inhibition or TRPV1 deletion will affect the fracture healing process is unclear. In this study, we found that the wild-type mice showed a well-remodeled fracture Callus, whereas TRPV1 knockout mice still had an obvious fracture gap with unresorbed Soft-Callus 4 weeks post-fracture. The number of osteoclasts was reduced in the TRPV1 knockout fracture Callus, and osteoclast formation and resorption activity were also impaired in vitro. TRPV1 deletion decreased the calcium oscillation frequency and peak cytoplasmic concentration in osteoclast precursors, subsequently reducing the expression and nuclear translocation of NFATc1 and downregulating DC-stamp, cathepsin K, and ATP6V. In addition, TRPV1 deletion caused reduced mRNA and protein expression of Runx2 and ALP in bone marrow stromal cells (BMSCs) and reduced calcium deposition in vitro. Our results suggest that TRPV1 deletion impairs fracture healing, and inhibited osteoclastogenesis and osteogenesis.
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TRPV1 deletion impaired fracture healing and inhibited osteoclast and osteoblast differentiation
SCIENTIFIC REPORTS, 2017Co-Authors: He Lin-hai, Lu Zhao, Liu Meng, He Yang, Xiao E., Zhang Ting, Yang Hua-qian, Yi ZhangAbstract:Fracture healing, in which osteoclasts and osteoblasts play important roles, has drawn much clinical attention. Osteoclast deficiency or decreased osteoblast activity will impair fracture healing. TRPV1 is a member of the Ca2+ permeable cation channel subfamily, and pharmacological inhibition of TRPV1 prevents ovariectomy-induced bone loss, which makes TRPV1 a potential target for osteoporosis. However, whether long term TRPV1 inhibition or TRPV1 deletion will affect the fracture healing process is unclear. In this study, we found that the wild-type mice showed a well-remodeled fracture Callus, whereas TRPV1 knockout mice still had an obvious fracture gap with unresorbed Soft-Callus 4 weeks post-fracture. The number of osteoclasts was reduced in the TRPV1 knockout fracture Callus, and osteoclast formation and resorption activity were also impaired in vitro. TRPV1 deletion decreased the calcium oscillation frequency and peak cytoplasmic concentration in osteoclast precursors, subsequently reducing the expression and nuclear translocation of NFATc1 and downregulating DC-stamp, cathepsin K, and ATP6V. In addition, TRPV1 deletion caused reduced mRNA and protein expression of Runx2 and ALP in bone marrow stromal cells (BMSCs) and reduced calcium deposition in vitro. Our results suggest that TRPV1 deletion impairs fracture healing, and inhibited osteoclastogenesis and osteogenesis.National Natural Science Foundation of China [81371117]; Beijing Natural Science Foundation [7152155]SCI(E)ARTICLE
René St-arnaud - One of the best experts on this subject based on the ideXlab platform.
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CYP24A1-deficient mice as a tool to uncover a biological activity for vitamin D metabolites hydroxylated at position 24.
The Journal of steroid biochemistry and molecular biology, 2010Co-Authors: René St-arnaudAbstract:The CYP24A1 enzyme (25-hydroxyvitamin D-24-hydroxylase) not only is involved in the catabolic breakdown of 1,25-dihydroxyvitamin D [1,25(OH)2D] but also generates the 24,25-dihydroxyvitamin D [24,25(OH)2D] metabolite. The biological activity of 24,25(OH)2D remains controversial. While in vitro studies suggest that primary cultures of rat rib chondrocytes respond to 24,25(OH)2D in a maturation-specific manner and that the metabolite is necessary for the cells to progress from a proliferating, immature status to a differentiated, 1,25(OH)2D-responsive stage, in vivo evidence to support this putative role remains lacking. Studies in chicken showed increases in serum levels of 24,25(OH)2D and of the renal mRNA levels of Cyp24a1 following fracture, suggesting a role for 24,25(OH)2D in fracture repair. The Cyp24a1-deficient mouse strain represents an invaluable tool to examine the putative role of 24,25(OH)2D in mammalian fracture repair. We have compared fracture repair between Cyp24a1-/- mice and wild-type controls. We have observed a delay in the mineralization of the cartilaginous matrix of the Soft Callus in Cyp24a1-/- mutant animals, accompanied by reduced expression of chondrocyte marker genes. These results show that Cyp24a1 deficiency delays fracture repair and strongly suggest that vitamin D metabolites hydroxylated at position 24, such as 24,25(OH)2D3, play an important role in the mechanisms leading to normal fracture healing.
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CYP24A1-deficient mice as a tool to uncover a biological activity for vitamin D metabolites hydroxylated at position 24 ☆
The Journal of Steroid Biochemistry and Molecular Biology, 2010Co-Authors: René St-arnaudAbstract:The CYP24A1 enzyme (25-hydroxyvitamin D-24-hydroxylase) not only is involved in the catabolic breakdown of 1,25-dihydroxyvitamin D [1,25(OH)2D] but also generates the 24,25-dihydroxyvitamin D [24,25(OH)2D] metabolite. The biological activity of 24,25(OH)2D remains controversial. While in vitro studies suggest that primary cultures of rat rib chondrocytes respond to 24,25(OH)2D in a maturation-specific manner and that the metabolite is necessary for the cells to progress from a proliferating, immature status to a differentiated, 1,25(OH)2D-responsive stage, in vivo evidence to support this putative role remains lacking. Studies in chicken showed increases in serum levels of 24,25(OH)2D and of the renal mRNA levels of Cyp24a1 following fracture, suggesting a role for 24,25(OH)2D in fracture repair. The Cyp24a1-deficient mouse strain represents an invaluable tool to examine the putative role of 24,25(OH)2D in mammalian fracture repair. We have compared fracture repair between Cyp24a1-/- mice and wild-type controls. We have observed a delay in the mineralization of the cartilaginous matrix of the Soft Callus in Cyp24a1-/- mutant animals, accompanied by reduced expression of chondrocyte marker genes. These results show that Cyp24a1 deficiency delays fracture repair and strongly suggest that vitamin D metabolites hydroxylated at position 24, such as 24,25(OH)2D3, play an important role in the mechanisms leading to normal fracture healing.