Cortical Remodeling Research Articles

Effects of Wnt5a Haploinsufficiency on Bone Repair

Wnt5a expression is upregulated during fracture repair and has previously been implicated as a potential regulator of skeletal development and bone mass accrual and maintenance. Our objective was to evaluate the function of Wnt5a in fracture healing. Femoral fracture experiments on Wnt5a and Wnt5a mice were carried out. To better understand the effect of the Wnt5a on bone repair, we evaluated radiographs using a previously validated qualitative scoring system and performed microcomputed tomography analyses. Histomorphometric analyses determined the temporal distribution of stroma, cartilage matrix, and woven bone in the fracture callus. Finally, we performed tartrate-resistant acid phosphatase (TRAP) immunohistochemical staining to visualize and quantify bone resorbing cells. Radiographic evaluations at day 21 demonstrated significantly higher cortical remodeling and bridging parameters for the Wnt5a group compared with the Wnt5a group. The bone volume fraction by microcomputed tomography was also significantly increased in Wnt5a mice. Histological and histomorphometric analyses showed that although Wnt5a mice exhibit decreased cartilage matrix production at day 7 postfracture, they displayed increased residual cartilaginous callus at days 14 and 21 compared with the Wnt5a group. In addition, the total number of multinucleated tartrate-resistant acid phosphatase-positive cells was significantly lower in the Wnt5a group than in the Wnt5a group. The data indicate that decreased Wnt5a signaling impaired proper fracture healing, possibly through decreased cartilaginous callus formation, and delayed cartilage matrix and mineralized tissue remodeling within the fracture callus.

Bone marrow levels of 25 hydroxy vitamin D are not depressed in cases of hip fracture compared with controls

There is little information on tissue as distinct from plasma levels of vitamin D metabolites in cases of hip fracture compared with controls. Femoral neck fractures in the elderly are associated with increased cortical remodelling and endosteal resorption, leading to regional increases in porosity and reduced cortical thickness. Vitamin D metabolites play a central role in the maintenance of normal serum calcium levels and may, through interactions with parathyroid hormone, exert an important influence on bone structure. To investigate whether hip fracture might be associated with tissue vitamin D deficiency, we have measured by radioimmunoassay the levels of 25 hydroxy vitamin D (25 (OH)D) in bone marrow samples extracted from the proximal femurs of 16 female subjects who had suffered fracture (mean age = 82.1 years, standard error (se) 1.9) and nine sex matched post mortem controls (mean age = 83.8 years, se 2.5). Twenty five (OH)D concentrations were significantly greater in the fracture cases (median = 3.7, IQR = 2.5-3.9 ng/g) than in the control group (median = 1.5, IQR = 0.9-2.3 ng/g; P = 0.0007, non-parametric Wilcoxon/Kruskal-Wallis test). It was suggested in the 1970s that bone loss and hip fracture risk in the UK were driven by vitamin D deficiency. Our results suggest that the alterations in femoral neck bone microstructure and remodelling in hip fracture cannot be assigned to the single cause of relative deficiency of vitamin D. Vitamin D deficiency or insufficiency may nevertheless increase remodelling and loss of bone tissue and contribute causally to a minority of hip fractures.

Acute stress exposure preceding transient global brain ischemia exacerbates the decrease in cortical remodeling potential in the rat retrosplenial cortex

Doublecortin (DCX)-immunoreactive (-ir) cells are candidates that play key roles in adult cortical remodeling. We have previously reported that DCX-ir cells decrease after stress exposure or global brain ischemia (GBI) in the cingulate cortex (Cg) of rats. Herein, we investigate whether the decrease in DCX-ir cells is exacerbated after GBI due to acute stress exposure preconditioning. Twenty rats were divided into 3 groups: acute stress exposure before GBI (Group P), non-stress exposure before GBI (Group G), and controls (Group C). Acute stress or GBI was induced by a forced swim paradigm or by transient bilateral common carotid artery occlusion, respectively. DCX-ir cells were investigated in the anterior cingulate cortex (ACC) and retrosplenial cortex (RS). The number of DCX-ir cells per unit area (mm2) decreased after GBI with or without stress preconditioning in the ACC and in the RS (ANOVA followed by a Tukey-type test, P<0.001). Moreover, compared to Group G, the number in Group P decreased significantly in RS (P<0.05), though not significantly in ACC. Many of the DCX-ir cells were co-localized with the GABAergic neuronal marker parvalbumin. The present study indicates that cortical remodeling potential of GABAergic neurons of Cg decreases after GBI, and moreover, the ratio of the decrease is exacerbated by acute stress preconditioning in the RS.

Perilesional osteopenia due to increased cortical remodelling following mandibular osteotomies and fractures

Perilesional osteopenia due to increased cortical remodelling following mandibular osteotomies and fractures

The Long Bone Deformity of Osteogenesis Imperfecta III: Analysis of Structural Changes Carried Out with Scanning Electron Microscopic Morphometry

The wedges of the mid-diaphyseal osteotomies carried out to correct the femoral and/or tibial native deformity in type III osteogenesis imperfecta (OI III) were used to study the remodeling patterns and lamellar organization at the level of the major deformity. Histology and scanning electron microscopy (SEM) morphology showed abnormal cortical remodeling characterized by the failure to form a cylinder of compact bone with a regular marrow canal. Atypical, flattened, and large resorption lacunae with a wide resorption front on one side and systems of parallel lamellae on the opposite side were observed, resembling those formerly reported as drifting osteons. SEM morphometry documented a higher percentage of nonossified vascular/resorption area (44.3 %) in OI than in controls (13.6 %), a lower density of secondary osteons, and lower values for the parameters expressing the individual osteon size. The mean osteon total area, the mean central canal area, and the mean osteon bone area of two selected, randomized populations of secondary osteons were significantly higher (p < 0.001, p = 0.028, and p < 0.001, respectively) in control bones than in OI. The mean ossified matrix area was not significantly different, but the mean secondary osteon number and mean density were higher in controls (both p < 0.001). Osteon wedges were carried out to correct the native deformity of OI III and morphologic analysis suggested that the abnormal remodeling pattern (with "drifting osteons") may result from the altered load and tensile stresses on the deformed tubular bones.

Prophase I Mouse Oocytes Are Deficient in the Ability to Respond to Fertilization by Decreasing Membrane Receptivity to Sperm and Establishing a Membrane Block to Polyspermy1

Changes occurring as the prophase I oocyte matures to metaphase II are critical for the acquisition of competence for normal egg activation and early embryogenesis. A prophase I oocyte cannot respond to a fertilizing sperm as a metaphase II egg does, including the ability to prevent polyspermic fertilization. Studies here demonstrate that the competence for the membrane block to polyspermy is deficient in prophase I mouse oocytes. In vitro fertilization experiments using identical insemination conditions result in monospermy in 87% of zona pellucida (ZP)-free metaphase II eggs, while 92% of ZP-free prophase I oocytes have four or more fused sperm. The membrane block is associated with a postfertilization reduction in the capacity to support sperm binding, but this reduction in sperm-binding capacity is both less robust and slower to develop in fertilized prophase I oocytes. Fertilization of oocytes is dependent on the tetraspanin CD9, but little to no release of CD9 from the oocyte membrane is detected, suggesting that release of CD9-containing vesicles is not essential for fertilization. The deficiency in membrane block establishment in prophase I oocytes correlates with abnormalities in two postfertilization cytoskeletal changes: sperm-induced cortical remodeling that results in fertilization cone formation and a postfertilization increase in effective cortical tension. These data indicate that cortical maturation is a component of cytoplasmic maturation during the oocyte-to-egg transition and that the egg cortex has to be appropriately primed and tuned to be responsive to a fertilizing sperm.

Amyloid-associated alterations in metabolic connectivity patterns in ADNI participants

While regional glucose hypometabolism is characteristic of Alzheimer's disease (AD), this feature has been shown to be primarily associated with the ApoE4 genotype, rather than fibrillar β-amyloid, during the pre-clinical/early stages of the disease process. However, derangements of metabolic connectivity are intimately related to β-amyloid plaque burden. In order to assess the specific alterations in metabolic connectivity in early disease, we have performed a quantitative analysis of correlation patterns derived from FDG positron emission tomography (PET) images from ADNI subjects with different levels of cortical β-amyloid. [18F]florbetapir PET, [18F]FDG PET, and 3D T1-weighted MR images were obtained from ADNI-GO/-2 study subjects classified as cognitively normal or mild cognitive impairment (MCI). PET volumes were registered to a customized MRI template in MNI stereotaxic space, and standardized uptake value ratio (SUVR) images were generated and projected onto each subject's cortical surface using Biospective's fully-automated PIANO TM image processing software. The amyloid burden for each subject was determined from a composite region-of-interest (ROI) on [18F]florbetapir images, and subjects were categorized into Amyloid-Low (Aβ L) and Amyloid-High (Aβ H) groups. We generated vertexwise correlation strength maps across the entire cerebral cortex, controlling for ApoE4 genotype, and assessed the relative alterations in short-/long-range and intra-/inter-hemispheric metabolic connections in each group. We observed statistically significant differences in short-/long-range and intra-/inter-hemispheric metabolic connections between the Aβ L and Aβ H groups in multiple cortical regions. For example, the entorhinal cortex showed greater reductions in inter- than intra-hemispheric correlations (especially with the contralateral medial temporal lobe, precuneus, and posterior lateral temporal-parietal cortex) in the Aβ H group. The angular gyrus demonstrated greater loss of long- than short-range metabolic correlations in the Aβ H group. We have employed metabolic connectivity analysis to examine disruptions of the cortical correlation architecture as a function of β-amyloid burden. The aberrant metabolic connections observed in the Aβ H group may be a consequence of variable spatio-temporal patterns of compensatory responses and/or cortical remodeling during the early stages of AD. The quantitative approach employed in this study may serve as a powerful, non-invasive imaging biomarker for early diagnosis/prognosis and objective evaluation of the efficacy of novel amyloid-lowering therapeutic agents.

Cognitive Reserve and Symptom Experience in Multiple Sclerosis: A Buffer to Disability Progression Over Time?

ObjectiveTo investigate the possible buffering effect of cognitive reserve on symptom experience for multiple sclerosis (MS) disease course. DesignSecondary analysis of longitudinal data from the North American Research Committee on MS Registry. SettingRegistry study and web-based supplemental survey. ParticipantsPeople with MS (N=859). InterventionsNot applicable. Main Outcome MeasuresTwo health outcome measures, the Symptom Inventory and the Performance Scales, were collected biannually over 1 and 6 years, respectively. Active and passive cognitive reserve was measured using the Stern Leisure Activities and the Sole-Padulles Childhood Enrichment tools, respectively. Linear regression, chi-square, multilevel random-effects modeling, and classification and regression tree modeling were used to compare cross-sectional means, disease course by cognitive reserve, longitudinal trajectories, and active cognitive reserve item endorsement by disability groups, respectively. ResultsPatients with high-active reserve had a lesser symptom burden than those with low-active reserve independent of passive reserve (P<.01). Cognitive reserve was associated with course of disease, such that high-active patients were overrepresented among relapsing-remitting patients, and underrepresented among patients with progressive disease (χ2=14.7, P<.03). Longitudinal modeling revealed a significant interaction of active reserve and time in mobility, fatigue, and overall disability in the whole sample (P<.05 in all comparisons). Among patients whose disability trajectories changed over time, active cognitive reserve was associated with less deterioration (P<.001). Passive cognitive reserve evidenced no effect in the longitudinal analyses. Active cognitive reserve scores across disability groups had a similar range but comprised different items, indicating that patients maintain active cognitive reserve with different activities as the disease progresses. ConclusionsOur findings suggest that active cognitive reserve is a buffer for functional limitation across disability groupings. Cognitive reserve may provide an alternative lens for thinking about the disease course of MS, providing a longer “runway” until disability accrual through cortical remodeling. Loss of cognitive reserve may explain the onset of progressive disease in MS.

Cadherin mechanotransduction in tissue remodeling.

Mechanical forces are increasingly recognized as central factors in the regulation of tissue morphogenesis and homeostasis. Central to the transduction of mechanical information into biochemical signaling is the contractile actomyosin cytoskeleton. Fluctuations in actomyosin contraction are sensed by tension sensitive systems at the interface between actomyosin and cell adhesion complexes. We review the current knowledge about the mechanical coupling of cell-cell junctions to the cytoskeleton and highlight the central role of α-catenin in this linkage. We assemble current knowledge about α-catenin's regulation by tension and about its interactions with a diversity of proteins. We present a model in which α-catenin is a force-regulated platform for a machinery of proteins that orchestrates local cortical remodeling in response to force. Finally, we highlight recently described fundamental processes in tissue morphogenesis and argue where and how this α-catenin-dependent cadherin mechanotransduction may be involved.

Cortical remodeling during menopause, rheumatoid arthritis, glucocorticoid and bisphosphonate therapy

Bone mass, bone geometry and its changes are based on trabecular and cortical bone remodeling. Whereas the effects of estrogen loss, rheumatoid arthritis (RA), glucocorticoid (GC) and bisphosphonate (BP) on trabecular bone remodeling have been well described, the effects of these conditions on the cortical bone geometry are less known. The present review will report current knowledge on the effects of RA, GC and BP on cortical bone geometry and its clinical relevance. Estrogen deficiency, RA and systemic GC lead to enhanced endosteal bone resorption. While in estrogen deficiency and under GC therapy endosteal resorption is insufficiently compensated by periosteal apposition, RA is associated with some periosteal bone apposition resulting in a maintained load-bearing capacity and stiffness. In contrast, BP treatment leads to filling of endosteal bone cavities at the epiphysis; however, periosteal apposition at the bone shaft seems to be suppressed. In summary, estrogen loss, RA and GC show similar effects on endosteal bone remodeling with an increase in bone resorption, whereas their effect on periosteal bone remodeling may differ. Despite over 50 years of GC therapy and over 25 years of PB therapy, there is still need for better understanding of the skeletal effects of these drugs as well as of inflammatory disease such as RA on cortical bone remodeling.

Long-term ongoing cortical remodeling after contralateral C-7 nerve transfer

Contralateral C-7 nerve transfer was developed for the treatment of patients with brachial plexus avulsion injury (BPAI). In the surgical procedure the affected recipient nerve is connected to the ipsilateral motor cortex, and the dramatic peripheral alteration may trigger extensive cortical reorganization. However, little is known about the long-term results after such specific nerve transfers. The purpose of this study was to investigate the long-term cortical adaptive plasticity after BPAI and contralateral C-7 nerve transfer. In this study, 9 healthy male volunteers and 5 male patients who suffered from right-sided BPAI and had undergone contralateral C-7-transfer more than 5 years earlier were included. Functional MRI studies were used for the investigation of long-term cerebral plasticity. The neuroimaging results suggested that the ongoing cortical remodeling process after contralateral C-7 nerve transfer could last for a long period; at least for 5 years. The motor control of the reinnervated limb may finally transfer from the ipsilateral to the contralateral hemisphere exclusively, instead of the bilateral neural network activation. The authors believe that the cortical remodeling may last for a long period after peripheral rearrangement and that the successful cortical transfer is the foundation of the independent motor recovery.

Contributions of Remodeling and Asymmetrical Growth to Vertebral Wedging in a Scoliosis Model

Study DesignWe performed a laboratory study of rats of 3 different ages with imposed angulation and compressive loading to caudal vertebrae to determine causes of vertebral wedging. ObjectivesThe purpose was to determine the percentage of total vertebral wedging that was caused by asymmetric growth, vertebral body, and epiphyseal wedging. Approval from the Institutional Animal Care and Use Committee, the University of Vermont, was obtained for the live animal procedures used in this study. Background SummaryVertebral wedging from asymmetrical growth (Hueter-Volkmann law) is reported to cause vertebral wedging in scoliosis with little attention to the possible contribution of bony remodeling (Wolff’s law). MethodsIn our study, an external fixator imposed a 30° lateral curvature and compression of 0.1 megapascal (MPa) in 5- and 14-week-old animals (Groups 1 and 2) and 0.2 MPa in 14- and 32-week-old animals (groups 3 and 4). Total vertebral wedging was measured from micro CT scans. Wedging due to asymmetrical growth and epiphyseal remodeling was calculated from fluorescent labels and the difference was attributed to vertebral body wedging. ResultsTotal vertebral wedging averaged 18°, 6°, 10° and 5° in Groups 1, 2, 3, and 4, respectively. Metaphyseal asymmetrical growth averaged 8°, 1°, 4°, 0° (44%, 17%, 40% and 0% of total). Epiphyseal wedging averaged 9°, 0°, 3°, and -1°. The difference (vertebral body) averaged 1°, 5°, 3°, and 7° (6%, 83%, 30% and 140% of total). The growth of the loaded vertebrae as a percentage of control vertebrae was 56%, 39% and 25% in Groups 1, 2 and 3; negligible in Group 4. Vertebral body cortical remodeling, with increased thickness and increased curvature on the concave side was evident in young animals and 0.2 MPa loaded older animals. ConclusionsWe conclude that asymmetrical growth was the largest contributor to vertebral wedging in young animals; vertebral body remodeling was the largest contributor in older animals. If, conversely, vertebral wedging can be corrected by appropriate loading in young and old animals, it has important implications for the nonfusion treatment of scoliosis.

Cytokinesis in Animal Cells

Cytokinesis, the final step in cell division, partitions the contents of a single cell into two. In animal cells, cytokinesis occurs through cortical remodeling orchestrated by the anaphase spindle. Cytokinesis relies on a tight interplay between signaling and cellular mechanics and has attracted the attention of both biologists and physicists for more than a century. In this review, we provide an overview of four topics in animal cell cytokinesis: (a) signaling between the anaphase spindle and cortex, (b) the mechanics of cortical remodeling, (c) abscission, and (d) regulation of cytokinesis by the cell cycle machinery. We report on recent progress in these areas and highlight some of the outstanding questions that these findings bring into focus.

Total Hip Arthroplasty Using Cementless Grit-Blasted Femoral Component: A Minimum 10-Year Follow-Up Study

The grit-blasted cementless Spotorno (CLS) stem, which has excellent survival rates up to 10 years, is widely used in total hip arthroplasty (THA). We investigated the survivorships of CLS stems in THA at a minimum follow-up of 10 years and sought to identify factors that influence outcomes. A total of 227 hips of 191 patients who underwent cementless THA with a CLS stem were retrospectively reviewed at a mean follow-up of 12.3 years. All patients were evaluated clinically and radiographically according to implant type and surgery-related and patient-related factors. Survivorship was 97.2% when femoral revision for any reason was defined as the end point. Femoral revisions were performed in 3 hips because of periprosthetic fractures. Survivorship for all hips, using revision for any reason as the end point, was 92.6%. Two metal-on-metal THAs were revised because of aseptic loosening or osteolysis around the cup. No significant differences were evident for type of stem, type of bearing surface, stem alignment, or patient-related factors. However, a canal fill index of 80% or less was found to affect cortical remodeling, subsidence, and a change in stem position of 5° or more, which indicates that care must be taken not to undersize stems. In addition, in view of the revisions performed, bearing surfaces appear to importantly influence THA survivorship.

Robust polarity specification operates above a threshold of microtubule dynamicity

Microtubule arrays effect cell polarisation by directing cellular cues for cortical remodelling and growth. Their function depends crucially on the intrinsic dynamic properties of constituent microtubules. Microtubule dynamicity is restricted to a certain range within the confines of a cellular geometry. Thus it is of great interest to determine whether rescaling of dynamic properties of microtubules has consequences for cell polarity. We constructed fission yeast strains exhibiting depressed microtubule dynamics by mutating the β-tubulin gene, nda3. This interfered with efficient accumulation of a polarity factor Tea1 at cell tips. Interestingly, the polarity machinery in the mutant cells was highly susceptible to perturbations. Simulations of growth zone formation followed by imaging of actin distribution showed a significantly delayed onset of bipolar growth. We propose that there exists a threshold of microtubule dynamicity that allows robust cellular polarisation.

Dynamic cortical actin remodeling by ERM proteins controls BCR microcluster organization and integrity

Dynamic cortical actin remodeling by ERM proteins controls BCR microcluster organization and integrity

ATP Enhances Neuronal Differentiation of PC12 Cells by Activating PKCα Interactions with Cytoskeletal Proteins

PKCα is a key mediator of the neuronal differentiation controlled by NGF and ATP. However, its downstream signaling pathways remain to be elucidated. To identify the signaling partners of PKCα, we analyzed proteins coimmunoprecipitated with this enzyme in PC12 cells differentiated with NGF and ATP and compared them with those obtained with NGF alone or growing media. Mass spectrometry analysis (LC-MS/MS) identified plectin, peripherin, filamin A, fascin, and β-actin as potential interacting proteins. The colocalization of PKCα and its interacting proteins increased when PC12 cells were differentiated with NGF and ATP. Peripherin and plectin organization and the cortical remodeling of β-actin were dramatically affected when PKCα was down-regulated, suggesting that all three proteins might be functional targets of ATP-dependent PKCα signaling. Taken together, these data demonstrate that PKCα is essential for controlling the neuronal development induced by NGF and ATP and interacts with the cytoskeletal components at two levels: assembly of the intermediate filament peripherin and organization of cortical actin.

Drosophila Mtm and class II PI3K coregulate a PI(3)P pool with cortical and endolysosomal functions

Reversible phosphoinositide phosphorylation provides a dynamic membrane code that balances opposing cell functions. However, in vivo regulatory relationships between specific kinases, phosphatases, and phosphoinositide subpools are not clear. We identified myotubularin (mtm), a Drosophila melanogaster MTM1/MTMR2 phosphoinositide phosphatase, as necessary and sufficient for immune cell protrusion formation and recruitment to wounds. Mtm-mediated turnover of endosomal phosphatidylinositol 3-phosphate (PI(3)P) pools generated by both class II and III phosphatidylinositol 3-kinases (Pi3K68D and Vps34, respectively) is needed to down-regulate membrane influx, promote efflux, and maintain endolysosomal homeostasis. Endocytosis, but not endolysosomal size, contributes to cortical remodeling by mtm function. We propose that Mtm-dependent regulation of an endosomal PI(3)P pool has separable consequences for endolysosomal homeostasis and cortical remodeling. Pi3K68D depletion (but not Vps34) rescues protrusion and distribution defects in mtm-deficient immune cells and restores functions in other tissues essential for viability. The broad interactions between mtm and class II Pi3K68D suggest a novel strategy for rebalancing PI(3)P-mediated cell functions in MTM-related human disease.

Conserved role for autophagy in Rho1-mediated cortical remodeling and blood cell recruitment

Dynamic regulation of cell shape underlies many developmental and immune functions. Cortical remodeling is achieved under the central control of Rho GTPase pathways that modulate an exquisite balance in the dynamic assembly and disassembly of the cytoskeleton and focal adhesions. Macroautophagy (autophagy), associated with bulk cytoplasmic remodeling through lysosomal degradation, has clearly defined roles in cell survival and death. Moreover, it is becoming apparent that proteins, organelles, and pathogens can be targeted for autophagic clearance by selective mechanisms, although the extent and roles of such degradation are unclear. Here we report a conserved role for autophagy specifically in the cortical remodeling of Drosophila blood cells (hemocytes) and mouse macrophages. Continuous autophagy was required for integrin-mediated hemocyte spreading and Rho1-induced cell protrusions. Consequently, hemocytes disrupted for autophagy were impaired in their recruitment to epidermal wounds. Cell spreading required ref(2)P , the Drosophila p62 multiadaptor, implicating selective autophagy as a novel mechanism for modulating cortical dynamics. These results illuminate a specific and conserved role for autophagy as a regulatory mechanism for cortical remodeling, with implications for immune cell function.

Effect of exogenous transforming growth factor-beta1 on radius defects healing of experimental rabbits repaired by coralline hydroxyapatite

Objective To investigate the effect of local injection of different doses of transforming growth factor-β1 (TGF-β1) on the radius defects healing of experimental rabbits repaired by coralline hydroxyapatite (CHA). Methods Forty-eight rabbits were randomly divided into groups A (n = 16), B (n = 16) and C (n = 16). After the models of repairing defect of the radii were established, CHA was implanted. Each repairing defect of the radii was locally injected with TGFβ1 (0 for group A, 20 for group B, and 200 ng for group C) for 4 weeks. At the 2nd, 4th, 8th and 16th week after surgery the implantments were harvested. The histological changes were observe by HE staining, and the defects healing was evaluated by radiograph, biomechanical tests at the 16th week after surgery and biomechanics of the radii was measured. Results In groups A, B and C, radiograph score was 1.50, 1.91, and 4. 80), bone healing quality score was 0. 51, 0. 88, and 1.70, cortical bone remodeling and conversion score was 0. 50, 0.82, and 2.39, and new bone formation score was 0.00, 1.22, and 4.56 respectively. Those in groups B and C were higher than in group A (P < 0.05 ). Biomechanical test revealed that in groups A, B and C, maximum load (N) was 180. 14, 251.17, and 273.20, and rigid (N/mm) was 348. 83, 549. 18, and 689. 19 respectively with the difference being statistically significant among the groups (P <0. 05). Conclusion The bone defects healing of experimental rabbits repaired by CHA can be significantly promoted by local application of exogenous TGF-β1 in a dose-dependent manner. Key words: Bone defects; Biomaterial; Transforming growth factor-betal ; Repair