Role In Fracture Healing Research Articles

The Vastus Intermedius Periosteal (VIP) Flap: A Novel Flap for Osteoinduction

Periosteum's role in fracture healing is widely recognized, and its function in bone tissue engineering shows great potential. Here we introduce a novel periosteal free flap to be used as an abundant source of periosteum in the engineering and repair of bone. The descending branch of the lateral femoral circumflex vessels were isolated on 11 fresh human cadavers, preserving perforators to the vastus intermedius muscle. A cuff of vastus intermedius and approximately 75% of the circumference of the femoral periosteum were harvested from 6 cm proximal to the knee to 8 cm distal to the greater trochanter. Flap pedicle length and periosteal dimensions were measured. The pedicle arteries were injected with radiopaque dye, and radiographs were taken. A musculoperiosteal flap was elevated with visible descending perforators in each case. Mean flap surface area was 128 cm(2) (+/-99-143 cm(2)). Average pedicle length was 8 cm (+/-6-11 cm). Dye injection confirmed that the flaps blood supply was the descending branch of the lateral femoral circumflex artery. This anatomical study confirms the vascular supply of this large musculoperiosteal flap. Future work will test its efficacy as an osteoinductive agent in bone repair and tissue engineering in humans.

Internal fixator for use in the mouse

Knockout techniques enable us to expand our knowledge about bonerepair processes. Since they require the use of mice, such studies necessitate the development of special technologies. Mechano-biological reactions play a determining role in fracture healing, and therefore controlled conditions of stability are essential. Achieving fixation with a low-mass implant avoids uncontrolled inertial loading and enables free ambulation. Aminiaturised version of conventional internal fixation as used in humans has been developed. The method consists of a plate-like internal fixator with locked screws. It permits compression fixation or splinting fixation at selectable levels of flexibility. A guide is used for standardised application of the fixator, the screws and the osteotomy. Locking the screws to the plate enables elevation of the fixator from the bone surface; therefore, minimal contact damage to the periosteal blood supply can be expected. The technology is now in use in several laboratories.

Promiscuous and Depolarization-Induced Immediate-Early Response Genes Are Induced by Mechanical Strain of Osteoblasts

Whereas mechanical stimulation is essential for bone homeostasis, straining of larger magnitude promotes bone regeneration by directing cell differentiation and proliferation and influencing the gene expression patterns of osteoblasts, which play a vital role in fracture healing by producing and mineralizing osteoid matrix. To elucidate the molecular mechanisms underlying the response of osteoblasts to mechanical strains comparable to those occurring during bone regeneration, MC3T3 S4 (MC4) osteoblast-like cells were stretched in vitro. Analysis based on microarray expression profiling during the first 8 h after straining showed 674 differentially expressed genes. The response to mechanical strain can be divided in an immediate-early response (IER) and later responses. Examination of the approximately 40 genes differentially expressed within the first 60 min, including 11 involved in regulating gene transcription, showed both promiscuous IER genes such as Fos that are upregulated by multiple extracellular stimuli, as well as a number of genes previously shown in neurons to be induced preferentially by depolarization (IPD-IER). Selected differentially expressed genes were validated after mechanical straining and KCl-induced depolarization. The effects of inhibitors for protein kinase A, mitogen-activated protein kinase, and calcineurin pathways were assessed in separate experiments by quantitative RT-PCR and shown to have differential effects on the response of MC4 cells and primary calvaria osteoblasts to both mechanical straining and KCl-induced depolarization. Therefore, our results showed the existence of two distinct pathways that mediate the IER of osteoblasts to large-magnitude mechanical straining and suggest that the IER to depolarizing stimuli is conserved in cell types as different as osteoblasts and neurons.

Growth hormone: does it have a therapeutic role in fracture healing?

Background: The role of growth hormone (GH) in augmenting fracture healing has been postulated for over half a century. GH has been shown to play a role in bone metabolism and this can be mediated directly or indirectly through IGF-I. Objectives: The use of GH was evaluated as a possible therapeutic agent in augmenting fracture healing. Method: A literature search was undertaken on GH and its effect on bone fracture healing primarily using MEDLINE/OVID (1950 to January 2009). Key words and phrases including ‘growth hormone’, ‘insulin like growth factor’, ‘insulin like growth factor binding protein’, ‘insulin like growth factor receptor’, ‘fracture repair’, ‘bone healing’, ‘bone fracture’, ‘bone metabolism’, ‘osteoblast’ and ‘osteoclast’ were used in different combinations. Manual searches of the bibliography of key papers were also undertaken. Results: Current evidence suggests a positive role of GH on fracture healing as demonstrated by in vitro studies on osteoblasts, osteoclasts and the crosstalk between the two. Animal studies have demonstrated a number of factors influencing the effect of GH in vivo such as dose, timing and method of administration. Application of this knowledge in humans is limited but clearly demonstrates a positive effect on fracture healing. Concern has been raised in the past regarding the safety profile of the pharmacological use of GH when used in critically ill patients. Conclusion: The optimal dose and method of administration is still to be determined, and the safety profile of this novel use of GH needs to be investigated prior to establishing its widespread use as a fracture-healing agent.

Management of a comminuted tibial fracture in a patient with primary lymphoedema

Multi-fragmented fractures of the distal tibia can be a diffi-cult injury to treat and when complicated by primary lym-phoedema they become a therapeutic challenge for thetrauma surgeon. Lymphoedema is described as tissue fluidaccumulation that arises as a result of impaired lymph drai-nage [12]. It is usually a chronic, unrelenting condition andcan interfere with the management of concomitant condi-tions or injuries including wound and fracture healing [2].Current management options for lymphoedema include pre-venting infection, limb positioning, exercise, compressiongarments and bandages, pneumatic pumps and lymphaticmassage.Lymphoedema praecox is the most common sub-type ofprimary lymphoedema [10] presenting between the ages of 2and 35 years old. The condition is almost ten times morecommon in women than in men and the oedema is usuallyunilateral and limited to the distal lower limb [1,11].It is well recognised that the soft tissue envelope plays animportant role in fracture healing and therefore fracturemanagementshouldincludeminimallyinvasivetechniquestolimit interference of the soft tissue. External fixators areemployedinthisregardandareoftenanexcellentsolutiontomanagement of both open and closed fractures. The Ilizarovexternal fixator has been well documented in such fracturemanagement [4,8]. It is a modular, fine wire and ring devisethat allows early loading and mobilisation [7].ToourknowledgetheuseoftheIlizarovexternalfixatorincases complicated by lymphoedema has not been describedin the English literature. We present a case of a patient withprimarylymphoedemapraecoxandacomminutedfractureofherdistaltibiatodescribeanapproachtothemanagementofthis complex dual pathology.

Identification of Novel Gene Expression in Healing Fracture Callus Tissue by DNA Microarray

Fracture healing requires controlled expression of thousands of genes. Only a small fraction of these genes have been isolated and fewer yet have been shown to play a direct role in fracture healing. The purpose of this study was threefold: (1) to develop a reproducible open femur model of fracture healing that produces consistent fracture calluses for subsequent RNA extraction, (2) to use this model to determine temporal expression patterns of known and unknown genes using DNA microarray expression profiling, and (3) to identify and validate novel gene expression in fracture healing. In the initial arm of the study, a total of 56 wild-type C57BL/6 mice were used. An open, stabilized diaphyseal femur fracture was created. Animals were killed at 1, 5, 7, 10, 14, 21, and 35 days after surgery and the femurs were harvested for analysis. At each time point, fractures were radiographed and sectioned for histologic analyses. Tissue from fracture callus at all stages following fracture yielded reproducibly large amounts of mRNA. Expression profiling revealed that genes cluster by function in a manner similar to the histologic stages of fracture healing. Based on the expression profiling of fracture tissue, temporal expression patterns of several genes known to be involved in fracture healing were verified. Novel expression of multiple genes in fracture callous tissue was also revealed including leptin and leptin receptor. In order to test whether leptin signaling is required for fracture repair, mice deficient in leptin or its receptor were fractured using the same model. Fracture calluses of mice deficient in both leptin or leptin receptor are larger than wild-type mice fractures, likely due to a delay in mineralization, revealing a previously unrecognized role of leptin signaling in fracture healing. This novel model of murine fracture repair is useful in examining both global changes in gene expression as well as individual signaling pathways, which can be used to identify specific molecular mechanisms of fracture healing.

P143. Effects of 5-Lipoxygenase Inhibition on Posterolateral Lumbar Spinal Fusion in the Rat Model

BACKGROUND CONTEXT: The process of osteogenesis after spinal arthrodesis is similar to that which occurs during fracture healing and heterotopic ossification. Previous work with fracture healing models has demonstrated increased healing rates with 5-lipoxygenase inhibition, which increases the cyclooxygenase pathway leading to increased prostaglandin formation. Although arachidonic acid metabolism has been shown to play a central role in fracture healing, little is known about the effects of modulation of the arachidonic acid pathway on spinal fusion healing.

Rapamycin affects early fracture healing in mice

The immunosuppressive drug rapamycin (RAPA) prevents rejection in organ transplantation by inhibiting interleukin-2-stimulated T-cell division. Rapamycin has also been suggested to possess strong anti-angiogenic activities linked to a decrease in production of vascular endothelial growth factor (VEGF). Angiogenesis and VEGF are thought to play a crucial role in fracture healing and as osteoporotic and traumatic fractures are common complications in immunosuppressed, organ transplantation patients, we conducted this study to analyze the effect of rapamycin treatment on bone repair. We investigated the effect of rapamycin treatment on bone repair in a murine closed femur fracture model using radiological, histomorphometric, immunohistochemical, biomechanical and protein biochemical analyses. X-ray analyses demonstrated that rapamycin treatment inhibits callus formation after two weeks of fracture healing. The radiologically observed lack of callus formation was confirmed by histomorphometric analyses, which revealed a significantly diminished callus size and a reduced amount of bone formation when compared with vehicle-treated controls. Biomechanical testing further demonstrated that rapamycin significantly reduces torsional stiffness of the callus. Interestingly, this effect was associated with decreased vessel formation; a diminished proliferation of osteoblasts, endothelial cells and periosteal cells; and a reduced VEGF expression in hypertrophic chondrocytes. After five weeks treatment, however, the negative impact of rapamycin on fracture healing was overcome. Thus, rapamycin initially delays fracture healing, most probably by inhibiting cell proliferation and neovascularization in the callus. These undesirable effects should be considered when rapamycin is administered to patients sustaining bone fractures.

Fracture induced mobilization and incorporation of bone marrow‐derived endothelial progenitor cells for bone healing

We recently reported that systemic administration of peripheral blood (PB) CD34+ cells, an endothelial progenitor cell (EPC)-enriched population, contributed to fracture healing via vasculogenesis/angiogenesis. However, pathophysiological role of EPCs in fracture healing process has not been fully clarified. Therefore, we investigated the hypothesis whether mobilization and incorporation of bone marrow (BM)-derived EPCs may play a pivotal role in appropriate fracture healing. Serial examinations of Laser doppler perfusion imaging and histological capillary density revealed that neovascularization activity at the fracture site peaked at day 7 post-fracture, the early phase of endochondral ossifification. Fluorescence-activated cell sorting (FACS) analysis demonstrated that the frequency of BM cKit+Sca1+Lineage- (Lin-) cells and PB Sca1+Lin- cells, which are EPC-enriched fractions, significantly increased post-fracture. The Sca1+ EPC-derived vasuculogenesis at the fracture site was confirmed by double immunohistochemistry for CD31 and Sca1. BM transplantation from transgenic donors expressing LacZ transcriptionally regulated by endothelial cell-specific Tie-2 promoter into wild type also provided direct evidence that EPCs contributing to enhanced neovascularization at the fracture site were specifically derived from BM. Animal model of systemic administration of PB Sca1+Lin- Green Fluorescent Protein (GFP)+ cells further confirmed incorporation of the mobilized EPCs into the fracture site for fracture healing. These findings indicate that fracture may induce mobilization of EPCs from BM to PB and recruitment of the mobilized EPCs into fracture sites, thereby augment neovascularization during the process of bone healing. EPCs may play an essential role in fracture healing by promoting a favorable environment through neovascularization in damaged skeletal tissue.

Bone morphogenetic proteins and their antagonists

Skeletal homeostasis is determined by systemic hormones and local factors. Bone morphogenetic proteins (BMPs) are unique because they induce the commitment of mesenchymal cells toward cells of the osteoblastic lineage and also enhance the differentiated function of the osteoblast. BMP activities in bone are mediated through binding to specific cell surface receptors and through interactions with other growth factors. BMPs are required for skeletal development and maintenance of adult bone homeostasis, and play a role in fracture healing. BMPs signal by activating the mothers against decapentaplegic (Smad) and mitogen activated protein kinase (MAPK) pathways, and their actions are tempered by intracellular and extracellular proteins. The BMP antagonists block BMP signal transduction at multiple levels including pseudoreceptor, inhibitory intracellular binding proteins, and factors that induce BMP ubiquitination. A large number of extracellular proteins that bind BMPs and prevent their binding to signaling receptors have emerged. The extracellular antagonists are differentially expressed in cartilage and bone tissue and exhibit BMP antagonistic as well as additional activities. Both intracellular and extracellular antagonists are regulated by BMPs, indicating the existence of local feedback mechanisms to modulate BMP cellular activities.

Osteopenia and impaired fracture healing in aged EP4 receptor knockout mice

The EP4 receptor, one of the subtypes of the prostaglandin E 2 (PGE 2) receptor, plays a critical role in the anabolic effects of PGE 2 on bone. However, its role in the maintenance of bone mass in aged animals and its role in fracture healing is not well known. Our studies addressed these issues by characterizing the skeletal phenotype of aged, EP4 receptor knockout (KO) mice, and by comparing fracture healing in aged KO mice versus wild type (WT) mice. There was no significant difference in body weight and femoral length between KO and WT mice at 15 to 16 months of age. Lower bone mass was seen radiographically in both axial and long bones of KO mice relative to WT mice. Micro-CT images of the distal femurs showed thinner cortices, fewer trabeculae, and a deteriorated trabecular network in KO mice. Total bone content, trabecular content, and cortical content, as assessed by pQCT in the distal femur, were lower in KO mice than WT controls. Histomorphometric measurements showed that trabecular bone volume and bone formation rate were significantly decreased whereas osteoclast number on trabecular surface and eroded surface on endocortical surface were significantly increased in KO mice. These data indicated that deleting the EP4 receptor resulted in an imbalance in bone resorption over formation, leading to a negative bone balance. The lower bone formation rate in EP4 KO mice was primarily due to decreased mineralizing surface, suggesting that the defect in overall bone formation was mainly due to the defect in osteoblastogenesis. Fracture healing was examined in KO and WT mice subjected to a transverse femoral fracture. Callus formation was significantly delayed as evidenced both radiographically and histologically in the fractured femurs of KO mice compared with those of WT mice. KO mice had significant decreases in total callus area, cartilaginous callus area, and bony callus area 2 weeks after fracture. By 4 weeks, complete bony bridging was seen in WT mice but not in KO mice. These data demonstrate that the absence of the EP4 receptor decreases bone mass and impairs fracture healing in aged male mice. Our findings indicate that the EP4 receptor is a positive regulator in the maintenance of bone mass and fracture healing.

In VivoGeneration of Cartilage from Periosteum

Periosteum has chondrogenic and osteogenic potential and plays an important role in fracture healing. The purpose of this study was to evaluate the reactive tissue formed after damaging the periosteum. Damaging the periosteum may be a way to generate ectopic cartilage or bone, which may be useful for the repair of articular cartilage and bone defects. Periosteum was bilaterally dissected from the proximal medial tibia of New Zealand White rabbits. Reactive periosteal tissue was harvested 10, 20, and 40 days postsurgery and analyzed for expression of collagen types I, II, and X, aggrecan, osteopontin, and osteonectin (by reverse transcription-polymerase chain reaction) and collagen types I and II (by immunohistochemistry). Reactive tissue was present in 93% of cases. Histologically, this tissue consisted of hyaline cartilage at follow-up days 10 and 20. Expression of collagen type II and aggrecan was present at 10 and 20 days postsurgery. Highest expression was at 10 days. Expression of collagen type X increased up to 20 days. No significant changes in the mRNA expression of osteopontin or osteonectin were observed. Immunohistochemistry confirmed the presence of cartilage, which was positive for collagen types I and II at 10 days and only for collagen type II at 20 days. At 20 days postsurgery the onset of bone formation was also observed. At 40 days postsurgery, the reactive tissue had almost completely turned into bone. The quality and amount of cartilage formed 10 days postsurgery make this technique potentially useful to fill large cartilage and bone defects. Also, periosteal callus formation, providing possible useful information for tissue engineering techniques, can be studied with this model.

Delayed fracture healing in iNOS knockout mice

Abstract Introduction: Inducible nitric oxide synthase (iNOS) is expressed in osteoblasts and is detected in the initial stages of fracture healing with expression localized to cells within the intra-membranous region of the fracture callus. In this study, we examined fracture healing in iNOS knockout (KO) and wild type (WT) mice with injury consisting of an open femur fracture. Methods: iNOS KO and WT mice (n = 10/group) were subjected to femur fracture under anesthesia. Histological and x-ray analyses as well as expression of osteoblast-related genes, such as osteoactivin, type I collagen and osteocalcin were performed using RT-PCR analysis. Results: Histological analysis of normal, non-fractured femurs from WT and iNOS mice showed an increase in trabecular bone volume in iNOS KO compared with WT littermates. At one and three weeks-post fracture, x-ray analysis showed a marked delay in fracture callus formation in iNOS KO compared with WT mice. These results were confirmed by histological analysis. In non-fractured femurs, osteoactivin, type I collagen and osteocalcin were over-expressed in iNOS KO compared with WT mice. In fractured femurs, osteoactivin, type I collagen, and osteocalcin expression were highly up-regulated in WT but not in iNOS KO mice. Conclusions: These data suggest that increased bone formation occurs after fracture in iNOS KO mice compared with WT mice and furthermore, that iNOS regulates osteoblast development and function. Thus, iNOS also plays a major role in fracture healing.

Increased expression of macrophage migration inhibitory factor during fracture healing in rats.

We previously reported that macrophage migration inhibitory factor (MIF) is expressed in osteoblasts in murine calvarial bone, and that MIF upregulates the expression of matrix metalloproteinase (MMP)-13 mRNA in osteoblasts and chondrocytes; however, its pathophysiological functions in bone have not been well understood. In this study, we used a rat femoral fracture model to examine the expression of MIF during the fracture healing process. Semiquantitative reverse transcription-polymerase chain reaction revealed that MIF mRNA was increased throughout the healing process. The level of MIF mRNA reached a maximum at day 4 postfracture, while MMP-13 mRNA became maximal at day 14 postfracture. Immunohistochemical analysis showed that MIF protein was present in the granulation tissues formed at the fracture site on day 4. On days 7 and 10, MIF was detected in the thickened periosteum, in osteoblastic cells that were present within the intramembranously formed bone under the thickened periosteum, and in chondrocytes within the cartilaginous callus. From day 14 to day 28, MIF was present in chondrocytes within the callus, although the level of MIF declined gradually over this period. On days 7 to 14, MMP-13 was also detected in osteoblastic cells within the intramembranously formed bone and in chondrocytes within the cartilaginous callus. The immunoreactivity for MMP-13 within chondrocytes decreased on days 21 and 28. These results suggest the possibility that MIF plays an important role in fracture healing in association with proliferation of stromal cells, and the induction of MMP-13 in osteoblasts or chondrocytes.

Testosterone is a Potent Accelerator of Fracture Healing: Early Structural Reconstruction and Improved Biomechanical Stability

Sex steroids (e. g., estrogen and testosterone) are known to have an integral function in skeletal homeostasis. Though they are known to improve bone strength, their role in fracture healing has not been well defined. The aim of this study was to examine the influence of testosterone on skeletal repair mechanisms, in order to test the hypothesis that sex steroids could be used to accelerate fracture healing after intramedullary nailing. Fracture healing was studied in 60 eugonadal female and male mice treated either with testosterone or placebo. To make mouse models accessible to fracture modulation studies that also allow biomechanical analysis, we modified the Einhorn tibial fracture model and developed a standardized closed femur fracture model. Mice treated with testosterone showed a significant acceleration of fracture healing. Callus size as assessed by contact-radiography and microCT was significantly enhanced. This beneficial effect could be demonstrated in female as well as in male mice. Furthermore, not only radiological and histological data demonstrated a positive morphological interference of testosterone with the fracture healing process, but also the functional competence, as assessed by three-point bending tests, was dramatically improved. This study shows that testosterone can be used to enhance and accelerate fracture healing.

Expression of connective tissue growth factor/hypertrophic chondrocyte-specific gene product 24 (CTGF/Hcs24) during fracture healing

Localization and expression of connective tissue growth factor/hypertrophic chondrocyte-specific gene product 24 (CTGF/Hcs24) during fracture healing in mouse ribs were investigated. In situ hybridization demonstrated that CTGF/Hcs24 mRNA was remarkably expressed, especially in hypertrophic chondrocytes and proliferating chondrocytes, in the regions of regenerating cartilage on days 8 and 14 after fracture. CTGF/Hcs24 mRNA was also expressed in proliferating periosteal cells in the vicinity of the fracture sites on days 2 and 8, and in cells in fibrous tissue around the callus on day 8. Northern blot analysis showed that expression of CTGF/Hcs24 mRNA was 3.9 times higher on day 2 of fracture healing than that on day 0. On day 8, it reached a peak of 8.6 times higher than that on day 0. It then declined to a lower level. Immunostaining showed that CTGF/Hcs24 was localized in hypertrophic chondrocytes and proliferating chondrocytes in the regions of regenerating cartilage, and in active osteoblasts in the regions of intramembranous ossification. Although CTGF/Hcs24 was abundant in the proliferating and differentiating cells (on days 8 and 14), immunostaining decreased as the cells differentiated to form bone (on day 20). CTGF/Hcs24 was also detected in cells in fibrous tissue, vascular endothelial cells in the callus, and periosteal cells around the fracture sites. These results suggest that CTGF/Hcs24 plays some role in fracture healing.

Hypoxia and VEGF up-regulate BMP-2 mRNA and protein expression in microvascular endothelial cells: implications for fracture healing.

The endothelium is a metabolically active secretory tissue, capable of responding to a wide array of environmental stimuli. Hypoxia and vascular endothelial growth factor (VEGF) are two components of the putative fracture microenvironment. This study investigated the role of hypoxia and VEGF on endothelial cell activation as it relates to the bone repair process. It was hypothesized that endothelial cells may have an important osteogenic role in fracture healing through the production of bone morphogenetic protein-2 (BMP-2), an osteogenic cytokine at the fracture site. Therefore, BMP-2 mRNA and protein expression in endothelial cells under hypoxia and/or VEGF treatment was studied. The authors observed a 2-fold to 3-fold up-regulation of BMP-2 mRNA expression in bovine capillary endothelial cells and human microvascular endothelial cells stimulated with hypoxia or rhVEGF. Furthermore, the combined effects of hypoxia and rhVEGF appeared to be additive on BMP-2 mRNA expression in bovine capillary endothelial cells. Actinomycin D and cycloheximide studies suggested that the increased mRNA expression was transcriptionally regulated. BMP-2 protein expression was up-regulated after 24 and 48 hours of treatment with either hypoxia or rhVEGF in bovine capillary endothelial cells. Surprisingly, the data suggest that endothelial cells may play not only an angiogenic role but also an osteogenic role by a direct stimulation of the osteoblasts, through the enhanced expression of a potent osteogenic factor, BMP-2, at the fracture site.

Differential Temporal Expression of Members of the Transforming Growth Factor β Superfamily During Murine Fracture Healing

Fracture healing is a unique postnatal repair process in which the events of endochondral and intramembranous bone formation follow a definable temporal sequence. The temporal patterns of messenger RNA (mRNA) expression for members of the transforming growth factor beta (TGF-beta) superfamily were examined over a 28-day period of fracture healing in mouse tibias. Bone morphogenetic protein 2 (BMP-2) and growth and differentiation factor 8 (GDF8) showed maximal expression on day 1 after fracture, suggesting their roles as early response genes in the cascade of healing events. Restricted expression of GDF8 to day 1, in light of its known actions as a negative regulator of skeletal muscle growth, suggests that it may similarly regulate cell differentiation early in the fracture healing process. GDF5, TGF-beta2, and TGF-beta3 showed maximal expression on day 7, when type II collagen expression peaked during cartilage formation. In contrast, BMP-3, BMP-4, BMP-7, and BMP-8 showed a restricted period of expression from day 14 through day 21, when the resorption of calcified cartilage and osteoblastic recruitment were most active. TGF-beta1, BMP-5 and BMP-6, and GDF10 were constitutively expressed from day 3 to day 21. However, during the same time period, GDF3, GDF6, and GDF9 could not be detected, and GDF1 was expressed at extremely low levels. These findings suggest that several members of the TGF-beta superfamily are actively involved in fracture healing and although they are closely related both structurally and functionally, each has a distinct temporal expression pattern and potentially unique role in fracture healing.

OSTEOINDUCTIVE GROWTH FACTORS IN PRECLINICAL FRACTURE AND LONG BONE DEFECTS MODELS

Fracture healing is a specialized form of the reparative process that the musculoskeletal system undergoes to restore skeletal integrity. This biologic process is a consequence of a complex cascade of biologic events that result in the restoration of bone tissue, allowing for the resumption of musculoskeletal function. Several growth-promoting substances have been identified at the site of skeletal injury and appear to play a physiologic role in fracture healing. This article reviews the effects of these osteoinductive growth factors on bone healing as elucidated by both preclinical in vivo fracture and diaphyseal defect healing models.

Potential role of insulinlike growth factors in fracture healing.

Several lines of evidence suggest that the insulinlike growth factors play a role in fracture healing. They promote cell proliferation and matrix synthesis by chondrocytes and osteoblasts, the two cell types largely responsible for the formation of fracture callus. Circulating levels of insulinlike growth factor I and bone mineral density decrease with increasing age, and administration of insulinlike growth factor I increases bone turnover in patients with low bone mineral density. Insulinlike growth factor I may accelerate the normal healing of intramembranous bone defects, inducing the healing of defects that otherwise would not heal. An important role of insulinlike growth factor I is to mediate many of the actions of growth hormone on the skeleton. Considerable effort has been devoted to testing the effect of growth hormone and, thereby, indirectly that of insulinlike growth factor I on fracture healing. These studies have yielded such disparate results that no general conclusions regarding the effect of growth hormone (or of growth hormone dependent insulinlike growth factor I) on fracture healing currently can be drawn. Additional studies are needed to clarify the role of the insulinlike growth factors in the fracture healing process and to determine how their anabolic actions can be enlisted in the clinical enhancement of fracture healing.