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In order to examine if autogenous BMP-2 expression is necessary for the osteogenic differentiation of marrow stromal cells, BMP-2 expression was inhibited using lentiviral transfection of a BMP2 shRNA. Inhibition of BMP2 expression decreased the expression of markers of terminal osteoblasts (osteocalcin, Runx2, osterix, APase activity, and mineral deposition), while the expression of transcription factors (Sox 9 and Msx2) that are seen in skeletal lineage progenitors were not effected. Rescue of osteogenic differentiation by the exogenous addition of either BMP7 or BMP2 recovered the levels of expression of osterix and APase and enhanced Sox9 and Msx2. However, BMP7 did not recover the expression of Runx2 and only partially recovered mineral deposition while the exogenous addition of BMP2 recovered all of these phenotypic properties. The effect of the loss of BMP2 expression on bone formation after marrow ablation lead to 80% loss of mineralized bone formation as assayed by microCT at day seven after surgery. Assay of same set of mRNAs as examined in vitro showed transient ~2 fold increase of Sox9 at day three after surgery in the shRNA BMP2 samples while at day seven osterix, Runx2, osteocalcin and Sox9 all showed ~50 to ~80% inhibition compared to expression in the NT (scrambled) treated samples. Interestingly, Msx2 showed ~10 fold elevation expression at seven days post surgery. Immunohistological examination of the cell populations found in the meduallary space three days after surgery with antibodies for CD146 and Sox9, showed equal numbers of cells expressing these skeletal stem markers in both control and shRNA treated specimens. These results demonstrate that: 1) BMP-2 is a central morphogenetic factor for the post natal osteogenic differentiation: 2) BMP2 does not effect the initial recruitment or expansion of skeletal stem cells in vivo: 3) Both BMP2 and BMP7 can both induce osterix and this transcription factor can promote ostegenic differentiation: 4) Expression of Runx2 is dependent on BMP2: 5) Both osterix and Runx2 are needed to fully promote osteogenic development. SA002See Friday Plenary number F002. SA003 Clinical Application of Resorbable Polymers in Guided BoneRegeneration. W. IP*. Orthopaedics & Traumatology, The University of Hong Kong, Hong Kong, Hong Kong. INTRODUCTION:Long segmental diaphyseal bone loss often results from high energy trauma like blast injury, osteomyelitis or wide excision of malignant conditions. Treatment of this long segmental diaphyseal defects remain a difficult clinical problem. In the literature, many authors have reported that bone loss more than 2.5 cm always require bone grafting. This is probably the critical size defect in human. Non-vascularized bone graft frequently fails if the defect is longer than 6-7 cm. 2.5 cm is probably the critical size defect in human and 7 cm is likely the critical size for non-vascularized bone graft. Various treatment methods are adopted currently to address this problem, including vascularized bone graft, distraction osteogene...
In order to examine if autogenous BMP-2 expression is necessary for the osteogenic differentiation of marrow stromal cells, BMP-2 expression was inhibited using lentiviral transfection of a BMP2 shRNA. Inhibition of BMP2 expression decreased the expression of markers of terminal osteoblasts (osteocalcin, Runx2, osterix, APase activity, and mineral deposition), while the expression of transcription factors (Sox 9 and Msx2) that are seen in skeletal lineage progenitors were not effected. Rescue of osteogenic differentiation by the exogenous addition of either BMP7 or BMP2 recovered the levels of expression of osterix and APase and enhanced Sox9 and Msx2. However, BMP7 did not recover the expression of Runx2 and only partially recovered mineral deposition while the exogenous addition of BMP2 recovered all of these phenotypic properties. The effect of the loss of BMP2 expression on bone formation after marrow ablation lead to 80% loss of mineralized bone formation as assayed by microCT at day seven after surgery. Assay of same set of mRNAs as examined in vitro showed transient ~2 fold increase of Sox9 at day three after surgery in the shRNA BMP2 samples while at day seven osterix, Runx2, osteocalcin and Sox9 all showed ~50 to ~80% inhibition compared to expression in the NT (scrambled) treated samples. Interestingly, Msx2 showed ~10 fold elevation expression at seven days post surgery. Immunohistological examination of the cell populations found in the meduallary space three days after surgery with antibodies for CD146 and Sox9, showed equal numbers of cells expressing these skeletal stem markers in both control and shRNA treated specimens. These results demonstrate that: 1) BMP-2 is a central morphogenetic factor for the post natal osteogenic differentiation: 2) BMP2 does not effect the initial recruitment or expansion of skeletal stem cells in vivo: 3) Both BMP2 and BMP7 can both induce osterix and this transcription factor can promote ostegenic differentiation: 4) Expression of Runx2 is dependent on BMP2: 5) Both osterix and Runx2 are needed to fully promote osteogenic development. SA002See Friday Plenary number F002. SA003 Clinical Application of Resorbable Polymers in Guided BoneRegeneration. W. IP*. Orthopaedics & Traumatology, The University of Hong Kong, Hong Kong, Hong Kong. INTRODUCTION:Long segmental diaphyseal bone loss often results from high energy trauma like blast injury, osteomyelitis or wide excision of malignant conditions. Treatment of this long segmental diaphyseal defects remain a difficult clinical problem. In the literature, many authors have reported that bone loss more than 2.5 cm always require bone grafting. This is probably the critical size defect in human. Non-vascularized bone graft frequently fails if the defect is longer than 6-7 cm. 2.5 cm is probably the critical size defect in human and 7 cm is likely the critical size for non-vascularized bone graft. Various treatment methods are adopted currently to address this problem, including vascularized bone graft, distraction osteogene...
The rare, long-lived radiotracer, Ca, measured by accelerator mass spectrometry in the urine or serum following incorporation into the bone provides an ultra-sensitive tool to assess changes in bone calcium balance in response to an intervention. Changes in bone balance can be followed for years with one small dose that is both radiologically and biologically non-invasive. Sequential interventions can be compared, with greater precision than they can with biochemical markers of bone turnover and with greater power than with bone densitometry. This method is especially useful to screen interventions over a period of weeks. The development and validation of this tool and its applications are reviewed. Mini abstract: Use ofCa measured in the urine or blood by accelerator mass spectrometry to assess bone balance provides a tool to compare the relative efficacy of multiple interventions. This perspective provides insights in the use of this novel method and comparisons with more traditional methods for evaluating the efficacy of interventions.
Our aim was to determine if zoledronic acid (ZA) changes (45)Ca pharmacokinetics and bone microstructure in irradiated, ovary-intact (I) and irradiated, ovariectomized mice (OVX), two groups with different patterns of skeletal damage. The hind limbs of I and OVX BALB/c mice received a single 16-Gy radiation dose, simulating pre- and postmenopausal female cancer patients undergoing radiation treatment. All I and OVX mice were radiolabeled with 15 μCi (45)Ca. Mice were treated with or without a 0.5 mg/kg injection of ZA. The time course of bone mineral remodeling was evaluated using a fecal (45)Ca assay, measured by liquid scintillation. A group of nonirradiated, intact mice were used for the longitudinal evaluation of (45)Ca biodistribution. Distal femur bone histomorphometric parameters were measured using microCT at 50 days post-ZA intervention. Most (45)Ca was incorporated into the skeleton and eliminated from the soft tissues within 3-5 days postirradiation, attaining a steady state of excretion at 25-30 days. ZA intervention in both groups resulted in a rapid decrease in fecal (45)Ca excretion. There was a significant difference in (45)Ca excretion in the OVX ± ZA (P = 0.005) group but not in the I ± ZA (P = 0.655) group. The rate of excretion of fecal (45)Ca was slower in the OVX + ZA compared to the I + ZA group (P = 0.064). (45)Ca assay is useful to monitor the time course of bone mineral remodeling after an antiresorptive intervention in irradiated mice, providing a basis to investigate bone effects of cancer therapy protocols. For equivalent doses of ZA, recovery may depend on the nature and degree of skeletal damage.
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