Global gene profiling reveals a downregulation of BMP gene expression in experimental atrophic nonunions compared to standard healing fractures.
ABSTRACT Nonunion is a challenging problem that may occur following certain bone fractures. However, there has been little investigation of the molecular basis of nonunions. Bone morphogenetic proteins (BMPs) play a significant role in osteogenesis. However, little is known about the expression patterns of BMPs in abnormal bone healing that results in nonunion formation. These facts prompted us to investigate and compare the gene expression patterns of BMPs and their antagonists in standard healing fractures and nonunions using rat experimental models. Standard closed healing fractures and experimental atrophic nonunions produced by periosteal cauterization at the fracture site were created in rat femurs. At postfracture days 3, 7, 10, 14, 21, and 28, total RNA was extracted from the callus of standard healing fracture and fibrous tissue of nonunion (n=4 per each time point and each group). Gene expression of BMPs, BMP antagonists, and other regulatory molecules were studied by methods including Genechip microarray and real-time quantitative RT-PCR. Gene expression of BMP-2, 3, 3B, 4, 6, 7, GDF-5, 7, and BMP antagonists noggin, drm, screlostin, and BAMBI were significantly lower in nonunions compared to standard healing fractures at several time points. Downregulation in expression of osteogenic BMPs may account for the nonunions of fracture. The balance between BMPs and their endogenous antagonists is critical for optimal fracture healing.
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ABSTRACT: The goal of soft tissue sarcoma management in the extremities is limb preservation, often combining surgery and external beam radiation. In patients who have undergone this therapy in the thigh, pathologic fracture is a serious, late complication. Non-union rates of 80–90% persist. No reliable biologic solution exists. A rat model combining one 18 Gy dose of radiation and diaphyseal periosteal excision reliably generates atrophic non-union of femoral fractures. We hypothesized that augmentation with OP-1 would increase union rate. Female Sprague-Dawley retired breeder rats were randomized to Control, Disease (external beam radiotherapy and periosteal stripping), Control + OP-1 (80 µg) and Disease + OP-1 groups. Animals underwent prophylactic fixation and controlled left femur fracture. Twenty-eight, 35, and 42 days post-fracture were end-points. Femora were analyzed using MicroCT, Back Scattered Electron Microscopy, and Histomorphometry. We observed a 2% union rate in the Disease groups (±OP-1 treatment). The union rate in Control groups was 97%. MicroCT demonstrated a lack of callus volume in Disease groups. Heterotopic ossification was observed in some OP-1 treated animals. The ineffectiveness of OP-1 in stimulating fracture union in this model suggests the endogenous repair mechanism has been compromised beyond the capabilities of osteoinductive biologics. © 2014 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop ResJournal of Orthopaedic Research 06/2014; 32(10). · 2.88 Impact Factor
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ABSTRACT: The aim of the study was to investigate the effect of a sustained release of bone morphogenetic protein2 (BMP-2) incorporated in a polymeric implant coating on bone healing. In vitro analysis revealed a sustained, but incomplete BMP-2 release until Day 42. For the in vivo study, the rat tibia osteotomy was stabilized either with control or BMP-2 coated wires, and the healing progress was followed by micro computed tomography (µCT), biomechanical testing and histology at Days 10, 28, 42 and 84. MicroCT showed an accelerated formation of mineralized callus, as well as remodeling and an increase of mineralized/total callus volume (p = 0.021) at Day 42 in the BMP-2 group compared to the control. Histology revealed an increased callus mineralization at Days 42 and 84 (p = 0.006) with reduced cartilage at Day 84 (p = 0.004) in the BMP-2 group. Biomechanical stiffness was significantly higher in the BMP-2 group (p = 0.045) at Day 42. In summary, bone healing was enhanced after sustained BMP-2 application compared to the control. Using the same drug delivery system, but a burst release of BMP-2, a previous published study showed a similar positive effect on bone healing. Distinct differences in the healing outcome might be explained due to the different BMP release kinetics and dosages. However, further studies are necessary to adapt the optimal release profiles to physiological mechanisms.International Journal of Molecular Sciences 05/2014; 15(5):8539-52. · 2.34 Impact Factor