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BackgroundBone repair is dependent on the presence of osteocompetent progenitors that are able to differentiate and generate new bone. Muscle is found in close association with orthopaedic injury, however its capacity to make a cellular contribution to bone repair remains ambiguous. We hypothesized that myogenic cells of the MyoD-lineage are able to contribute to bone repair.MethodsWe employed a MyoD-Cre+:Z/AP+ conditional reporter mouse in which all cells of the MyoD-lineage are permanently labeled with a human alkaline phosphatase (hAP) reporter. We tracked the contribution of MyoD-lineage cells in mouse models of tibial bone healing.ResultsIn the absence of musculoskeletal trauma, MyoD-expressing cells are limited to skeletal muscle and the presence of reporter-positive cells in non-muscle tissues is negligible. In a closed tibial fracture model, there was no significant contribution of hAP+ cells to the healing callus. In contrast, open tibial fractures featuring periosteal stripping and muscle fenestration had up to 50% of hAP+ cells detected in the open fracture callus. At early stages of repair, many hAP+ cells exhibited a chondrocyte morphology, with lesser numbers of osteoblast-like hAP+ cells present at the later stages. Serial sections stained for hAP and type II and type I collagen showed that MyoD-lineage cells were surrounded by cartilaginous or bony matrix, suggestive of a functional role in the repair process. To exclude the prospect that osteoprogenitors spontaneously express MyoD during bone repair, we created a metaphyseal drill hole defect in the tibia. No hAP+ staining was observed in this model suggesting that the expression of MyoD is not a normal event for endogenous osteoprogenitors.ConclusionsThese data document for the first time that muscle cells can play a significant secondary role in bone repair and this knowledge may lead to important translational applications in orthopaedic surgery.Please see related article: http://www.biomedcentral.com/1741-7015/9/136

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Neurofibromatosis type 1 (NF1) is a common genetic condition caused by mutations in the NF1 gene. Patients often suffer from tissuespecific lesions associated with local double-inactivation of NF1. In this study, we generated a novel fracture model to investigate the mechanism underlying congenital pseudarthrosis of the tibia (CPT) associated with NF1. We used a Cre-expressing adenovirus (AdCre) to inactivate Nf1 in vitro in cultured osteoprogenitors and osteoblasts, and in vivo in the fracture callus of Nf1 flox/flox and Nf1 flox/À mice.

Recent studies suggest a possible role for inhibitors of sclerostin such as sclerostin antibody (Scl-Ab) as an anabolic treatment for osteoporosis. Since Scl-Ab has also been shown to potentiate bone repair, we examined the effect of Scl-Ab treatment in a metaphyseal defect repair model in ovariectomized (OVX) rats. Four weeks after OVX or sham surgery, 3 mm circular defects were created bilaterally in the proximal tibia of all rats. After defect surgery, Saline or 25 mg/kg Scl-Ab was administered twice weekly for 3 weeks. Of note, healing was advanced in the 1-week post-defect surgery in OVX controls over Sham controls, with increases in bone volume and fluorochrome labeling observed. However, by week 2, OVX controls fell significantly behind in the repair response compared with Sham controls. Scl-Ab treatment significantly increased bone volume in the defect in OVX rats over the 3-week time course as examined by either microCT or histology. Significant increases in bone formation via fluorochrome labeling of the new bone were observed with Scl-Ab treatment, while osteoclast parameters were not different. With its powerful anabolic potential, bone-specific activity, and potential for low dosing frequency, Scl-Ab treatment could provide enhanced bone repair, particularly in situations of compromised bone repair such as osteoporotic bone. Keywords: sclerostin; bone; defect; repair; formation Sclerostin is a negative regulator of bone formation which was discovered through the detection of a mutation in the SOST gene in patients diagnosed with the high bone mass disease, sclerosteosis.1 Parallel to the human disease, mice with a targeted deletion of SOST demonstrate an extremely high bone mass phenotype, highlighting the conservation of sclerostin's negative regulation of bone formation through evolution.2 One mechanism of sclerostin action is via direct antagonism of the Wnt/b-catenin pathway, resulting in inhibition of osteoblast formation and differentiation from precursor cells.3 Sclerostin may also act as an antagonist of bone morphogenetic proteins. 4 The expression of sclerostin is largely restricted to osteocytes, therefore, its effects are largely selective to skeletal tissue. 5,6 It has recently been reported that inhibition of sclerostin with a neutralizing sclerostin antibody (Scl-Ab) increased bone formation and restored bone mass and bone strength in the osteopenic, ovariectomized (OVX) rat model. 7 Scl-Ab was also shown to prevent bone loss associated with limb disuse in rats. 8 In addition, Scl-Ab treatment has led to increases in bone formation, bone mass, and bone strength in aged male rats and in nonhuman primate models.9,10 Similarly, it was reported that Scl-Ab significantly increased bone formation markers and bone mineral density (BMD), and significantly decreased bone resorption markers after a single injection in healthy men and post-menopausal women. 11In addition to its efficacy in preclinical models of osteoporosis, Scl-Ab treatment has been reported to enhance fracture healin...