Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
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J. Bone Miner. Res. · Jul 2014
Core binding factor beta (Cbfβ) controls the balance of chondrocyte proliferation and differentiation by upregulating Indian hedgehog (Ihh) expression and inhibiting parathyroid hormone-related protein receptor (PPR) expression in postnatal cartilage and bone formation.
Core binding factor beta (Cbfβ) is essential for embryonic bone morphogenesis. Yet the mechanisms by which Cbfβ regulates chondrocyte proliferation and differentiation as well as postnatal cartilage and bone formation remain unclear. Hence, using paired-related homeobox transcription factor 1-Cre (Prx1-Cre) mice, mesenchymal stem cell-specific Cbfβ-deficient (Cbfβ(f/f) Prx1-Cre) mice were generated to study the role of Cbfβ in postnatal cartilage and bone development. ⋯ Chromatin immunoprecipitation (ChIP) analysis and promoter luciferase assay demonstrated that the Runx/Cbfβ complex binds putative Runx-binding sites of the Ihh promoter regions, and also the Runx/Cbfβ complex directly upregulates Ihh expression at the transcriptional level. Consistently, the expressions of Ihh target genes, including CyclinD1, Ptc, and Pthlh, were downregulated in Cbfβ-deficient chondrocytes. Taken together, our study reveals not only that Cbfβ is essential for chondrocyte proliferation and differentiation for the growth and maintenance of the skeleton in postnatal mice, but also that it functions in upregulating Ihh expression to promoter chondrocyte proliferation and osteoblast differentiation, and inhibiting PPR expression to enhance chondrocyte differentiation.
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J. Bone Miner. Res. · Jun 2014
Randomized Controlled TrialPamidronate attenuates muscle loss after pediatric burn injury.
Children who are burned >40% total body surface area lose significant quantities of both bone and muscle mass because of acute bone resorption, inflammation, and endogenous glucocorticoid production, which result in negative nitrogen balance. Because administration of the bisphosphonate pamidronate within 10 days of the burn injury completely prevents the bone loss, we asked whether muscle protein balance was altered by the preservation of bone. We reviewed the results from 17 burned pediatric subjects previously enrolled in a double-blind randomized controlled study of pamidronate in the prevention of post-burn bone loss and who were concurrently evaluated for muscle protein synthesis and breakdown by stable isotope infusion studies during the acute hospitalization. ⋯ Muscle fiber diameter was significantly greater in the pamidronate subjects and leg strength at 9 months post-burn was not different between subjects who received pamidronate and normal physically fit age-matched children studied in our lab. Leg strength in burned subjects who served as controls tended to be weaker, although not significantly so. If substantiated by a larger study, these results suggest that bone may have a paracrine mechanism to preserve muscle and this finding may have implications for the treatment of sarcopenia in the elderly.
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J. Bone Miner. Res. · Jun 2014
Bisphosphonates inhibit osteosarcoma-mediated osteolysis via attenuation of tumor expression of MCP-1 and RANKL.
Osteosarcoma is the most common primary malignant tumor of bone and accounts for around 50% of all primary skeletal malignancies. In addition to novel chemotherapies, there is a need for adjuvant therapies designed to inhibit osteosarcoma proliferation and tumor-induced osteolysis to attenuate tumor expansion and metastasis. As such, studies on the efficacy of bisphosphonates on human osteosarcoma are planned after feasibility studies determined that the bisphosphonate zoledronic acid (ZOL) can be safely combined with conventional chemotherapy. ⋯ In vivo, these findings also correlated with significant reduction in osteosarcoma growth. ZOL attenuates tumor-induced osteolysis, not only through direct inhibition of osteoclasts, but also through direct actions on tumor expression of osteoclast activators. These data provide insight regarding the effect of ZOL on osteosarcoma essential for designing the planned upcoming prospective randomized trials to determine the efficacy of bisphosphonates on osteosarcoma in humans.
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J. Bone Miner. Res. · Apr 2014
Assessment of bone microarchitecture in postmenopausal women on long-term bisphosphonate therapy with atypical fractures of the femur.
Reports of atypical femoral fractures (AFFs) in patients receiving long- term bisphosphonate therapy have raised concerns regarding the genesis of this rare event. Using high-resolution peripheral quantitative computed tomography (HR-pQCT), we conducted a study to evaluate bone microarchitecture in patients who had suffered an AFF during long-term bisphosphonate treatment. The aim of our study was to evaluate if bone microarchitecture assessment could help explain the pathophysiology of these fractures. ⋯ This suggests that risk of developing an atypical fracture is not related to bone microarchitecture deterioration. Our results indicate that there may be other individual factors predisposing to atypical fractures in patients treated with bisphosphonates, and that those are independent of bone microarchitecture. In the future, identification of those factors could help prevent and understand the complex physiopathology of these rare events.