GDF5 is associated with a variety of skeletal malformations due to gain or loss of function mutations

Growthand Differentiation Factor 5 (GDF5) is a well-characterized member of the TGF-s superfamily and plays a key role in chondrogenesis, growth and patterning of the developing vertebrate skeleton. Several human limb malformations are known to result from mutations in the GDF5 gene, like brachydactylies (BD) characterized by the reduction or partial loss of carpal and tarsal elements or proximal symphalangism (SYM) and multiple synostosis syndrome (SYNS1), both characterized by fusion of the joints in the hands and feet. We hypothesize that this diverse phenotypic spectrum is due to an imbalance of protein–protein interactions between ligand, the transmembrane receptors and the extracellular acting antagonists. Functional studies including in vitro chondrogenesis and reporter gene assays as well as Surface Plasmon Resonance measurements were used to examine the specific molecular pathogenesis of GDF5 mutations associated with the resulting phenotype. We show that GDF5 loss of function is associated with brachydactyly, whereas gain of function mutations are associated with joint fusions. ⁎ both first authors. doi:10.1016/j.bone.2012.08.026 O26 Responses of osteocalcin to oral glucose load in insulin-resistant and non-insulin-resistant women V. Schwetz, E. Lerchbaum, N. Schweighofer, N. Hacker, O. Trummer, O. Borel, T. Pieber, R. Chapurlat, B. Obermayer-Pietsch Division of Endocrinology and Metabolism, Department of Internal Medicine, Medical University of Graz, Graz, Austria INSERM UMR 1033, Universite de Lyon, Hopital Edouard Herriot, France Abstract: Introduction: Osteoblast-produced osteocalcin (OC) might play a role in Introduction: Osteoblast-produced osteocalcin (OC) might play a role in energy metabolism and in the regulatory circuit between pancreas and osteoblasts. Aim: The aim was to evaluate the effect of a 75 g oral glucose tolerance test (OGTT) on total OC, undercarboxylated osteocalcin (ucOC), and carboxylated osteocalcin (cOC) in insulin-resistant (IR) and non-insulin-resistant (nonIR) premenopausal women. Further, the relationship of changes in total OC, ucOC, and cOC with AUCinsulin and Matsuda index was examined. Methods: In this cross-sectional study, 105 premenopausal women underwent OGTT (21 IR (HOMA-IRN2) and 84 nonIR). After glucose load, changes in total OC, ucOC, and cOC were evaluated after 30, 60, and 120 min. Results: At baseline, IR women had significantly lower levels of total OC, cOC, and ucOC. In nIR women, total OC decreased by 20.7% from 18.4 ng/ml [14.8–24.9] at baseline to 14.6 ng/ml [10.9–17.8] after 120 min; ucOC decreased by 21.9% from 3.2 ng/ml [2.3–4.6] to 2.5 ng/ml [1.7–3.5]; cOC decreased by 27.0% from 15.2 ng/ml [12.3–20.6] to 11.1 ng/ml [9.0–15.1] (pb0.001, respectively). In IR women, neither decreased significantly. In stepwise linear regression analyses, after adjusting for age and BMI, the declines in OC and cOC upon glucose load were predictors of AUCinsulin (deltaOC: beta=0.301, p=0.001; deltacOC: beta=0.315, pb0.001) and Matsuda index (ΔOC: beta=−0.235, p=0.003; deltacOC: beta=−0.245, p=0.002). Conclusions: Glucose intake in nonIR women has a short-term lowering effect on the levels of OC, ucOC, and cOC. These rapid effects reflect the interaction of bone and glucose metabolism. In IR women these parameters seem constantly suppressed, suggesting insulin resistance in osteoblasts. doi:10.1016/j.bone.2012.08.027 O27 Overlapping and follow-up of alendronate to teriparatide treatment results in maintenance of excess BMD gain C. Muschitz, R. Kocijan, A. Fahrleitner-Pammer, S. Lung, H. Resch Medical Department II — VINFORCE, St. Vincent Hospital, Vienna, Austria Medical University Graz, Division of Endocrinology and Metabolism, Department of Internal Medicine, Austria Department of Radiology, St. Vincent Hospital, Vienna, Austria Abstract: Purpose: After 9 months of teriparatide (TPTD) treatment the combination of alendronate (ALN) and TPTD for the consecutive 9 months results in enhanced bone mineral density (BMD) gain, mostly at cortical sites, compared with 18 months of TPTD monotherapy. Administration of raloxifene (RAL) instead of ALN was less advantageous. Both antiresorptive combination therapies maintain TPTD Purpose: After 9 months of teriparatide (TPTD) treatment the combination of alendronate (ALN) and TPTD for the consecutive 9 months results in enhanced bone mineral density (BMD) gain, mostly at cortical sites, compared with 18 months of TPTD monotherapy. Administration of raloxifene (RAL) instead of ALN was less advantageous. Both antiresorptive combination therapies maintain TPTD induced bone formation to some extent, while bone resorption declines more on ALN than RAL. Our aim was to investigate the BMD changes for the 12 months after cessation of TPTD treatment but with continuation of the respective antiresorptive treatment. Methods: 125 postmenopausal women (mean age 71.7±8.5 years, 91.5% prevalent fractures, 95.7% prior antiresorptive treatment) were prospectively randomized after 9 months of TPTD treatment into three open-label groups for another 9 months: ALN (70 mg/week, 41 patients) or RAL (60 mg/day, 37 patients) added to TPTD treatment or no additional medication (TPTD monotherapy, 47 patients). After TPTD termination, patients were treated with the respective antiresorptive agent for another 12 months (extension phase). All subjects received 1000 mg calcium and 800 IU vitamin D daily. Serum levels of intact amino terminal propeptide of type I procollagen (PINP) and type 1 collagen cross-linked C-telopeptide (CTX) as well as BMD measured by DXA at lumbar spine, total hip and femoral neck were evaluated at randomization, end of TPTD treatment, and at 6 and 12 months in the extension phase. Results: Lumbar spine BMD increased in all groups during the extension phase. Compared with values at the time of randomization, at the end of the extension phase, the increase in lumbar spine BMD was significantly higher in the ALN (10.1±7.3%, p=0.002) and RAL (8.4±5.4%, p=0.019) groups than in the TPTD monotherapy group (4.5±10.3%). At total hip addition of RAL (0.5±3.8%) did not alter the effects of TPTD monotherapy on BMD (0.5±5.5%). Addition of ALN resulted in a superior increase in both total hip BMD (8.2±5.8%) and femoral neck BMD (9.1±10.1%, pb0.001 for both) compared with RAL or TPTD alone. PINP and CTX declined in all groups in the extension phase reaching the lowest concentrations in the ALN combination group. Conclusion: Our data suggest that continuation of ALN after its addition to the second 9 months of an 18-month TPTD treatment cycle resulted in a robust and enhanced BMD increase especially in the hip region. doi:10.1016/j.bone.2012.08.028 O28 Serum sclerostin levels, bone turnover markers and body composition in mild, moderate and severe osteogenesis imperfecta R. Kocijan, C. Muschitz, K. Amrein, A. Fahrleitner-Pammer, P. Pietschmann, J. Haschka, S. Dinu, H. Resch The VINFORCE Study Group, St. Vincent Hospital, Medical Department II, Academic Teaching Hospital of Medical University of Vienna, Austria Department of Internal Medicine, Division of Endocrinology and Metabolism, Medical University of Graz, Austria Deptartment of Pathophysiology Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Austria Central Laboratory St. Vincent Group, Vienna, Austria Abstract: Objectives: Osteogenesis imperfecta (OI) is a genetic disorder, charObjectives: Osteogenesis imperfecta (OI) is a genetic disorder, characterized by increased bone fragility. Follow up of disease by biochemical markers or radiological techniques is currently not reliable. Methods: Serum sclerostin levels and bone turnover markers (BTM) were assessed in 23 adult patients with OI. OI total was divided into the mild OI I and the moderate and severe OI III/IV group. Body composition including fat distribution and bone mineral density (BMD) were measured by dual-energy X-ray absorptiometry (DXA). All data were compared to a healthy age Abstracts S10