Acute phosphate restriction leads to impaired fracture healing and resistance to BMP-2

Abstract

Hypophosphatemia leads to rickets and osteomalacia, the latter of which results in decreased biomechanical integrity of bones, accompanied by poor fracture healing. Impaired phosphate-dependent apoptosis of hypertrophic chondrocytes is the molecular basis for rickets. However, the underlying pathophysiology of impaired fracture healing has not been characterized previously. To address the role of phosphate in fracture repair, mice were placed on a phosphate-restricted diet 2 days prior to or 3 days after induction of a mid-diaphyseal femoral fracture to assess the effects of phosphate deficiency on the initial recruitment of mesenchymal stem cells and their subsequent differentiation. Histologic and micro-computed tomographic (µCT) analyses demonstrated that both phosphate restriction models dramatically impaired fracture healing primarily owing to a defect in differentiation along the chondrogenic lineage. Based on Sox9 and Sox5 mRNA levels, neither the initial recruitment of cells to the callus nor their lineage commitment was effected by hypophosphatemia. However, differentiation of these cells was impaired in association with impaired bone morphogenetic protein (BMP) signaling. In vivo ectopic bone-formation assays and in vitro investigations in ST2 stromal cells confirmed that phosphate restriction leads to BMP-2 resistance. Marrow ablation studies demonstrate that hypophosphatemia has different effects on injury-induced intramembranous bone formation compared with endochondral bone formation. Thus phosphate plays an important role in the skeleton that extends beyond mineralized matrix formation and growth plate maturation and is critical for endochondral bone repair. © 2010 American Society for Bone and Mineral Research.

A2B Adenosine Receptor Promotes Mesenchymal Stem Cell Differentiation to Osteoblasts and Bone Formation in Vivo

“…Specimen Harvesting-The procedures have been previously described (30). Briefly, the animals were euthanized by CO 2 asphyxiation.…”

“…Quantitative Microcomputed Tomography-Micro-CT analysis of mouse femurs has been previously described (30). Fractured bones were prepared for scanning by removal of the intramedullary pins.…”

Advances and Promises of Nutritional Influences on Natural Bone Repair

“…Calcium deficiency does not appear to significantly impact fracture healing, which is likely a result of stored calcium that is liberated from the intact skeleton following fracture. Along with calcium, the hydroxyapatite inorganic component of bone also requires phosphorus, and consumption of phosphate‐restricted diets negatively impacts secondary fracture healing . Severe phosphate deficiency impairs the proliferation and differentiation of mesenchymal progenitor cells, leading to an overall decrease in callus volume and an early, yet sustained increase in callus cartilage in mice with femoral fractures .…”

The Significance of Serum Phosphate Level on Healing Index and Its Relative Effects in Skeletally Immature and Mature Patients with Hypophosphatemic Rickets

“…BMPs have been shown to play important roles in embryonic organ development, limb formation, and fracture healing including those that exhibit nonunion [1, 16–18]. In the context of fracture healing, BMPs bind to mesenchymal stem cells and promote their proliferation and differentiation into osteoprogenitor cells, making them truly osteoinductive [19].…”