Bone Abstracts

Screening gene function in vivo is a powerful approach to discover novel drug targets in the human genome (Nat Rev Drug Discov 2 38–51, 2003). We present data for 3776 distinct gene knockout (KO) mouse lines with viable adult homozygous mice generated using both gene-trapping and homologous recombination technologies. Bone mass was determined from PIXImus DEXA scans of male and female mice at 14 weeks of age and by microCT analyses of bones from ...

Selective p38α inhibitors have been found to prevent bone loss induced by estrogen deficiency but implicated mechanisms remained to be identified. The p38 MAPK pathway has been suggested to influence bone resorption at different regulatory levels. In osteoblasts, p38α has been reported to be involved in the production of osteoclastogenic interleukin 6 and Rankl in response to various bone-resorptive agents in vitro. Therefore, we investigated whether p38&#94...

Osteoblasts produce protein-crosslinking enzymes, transglutaminase 2 (TG2) and factor XIIIA (FXIIIA), which regulate fibronectin matrix stabilization and osteoblast differentiation in vitro. To examine if they are important in bone remodeling and in maintenance of bone quality and mass in vivo, we performed skeletal phenotyping of Tgm2−/− and F13a1−/− mice and generated a double-null Tgm2</em...

Glucocorticoids (GC) are effective drugs in the treatment of inflammatory diseases, including various forms of arthritis. However, their use is limited by negative effects on bone mass and strength, resulting in increased osteoporotic fractures. Conditional knockout mice demonstrated that the GR in osteoblasts is essential for GC-dependent bone loss. Recent studies show that GC profoundly inhibit Wnt signaling by stimulating the expression of Wnt antagonists such as dickkopf-1...

Sclerostin, a Wnt signaling antagonist encoded by the SOST gene, negatively regulates osteoblasts and inhibits bone formation. Mechanical loading, which induces bone formation, leads to a decrease in sclerostin levels. Recently, neutralizing antibodies against sclerostin were tested successfully for the treatment of osteoporosis in rodents. However, sclerostin is not the only signal involved in mechanotransduction. Therefore we investigated whether treatment with sclerostin an...

Mechanical stimulation triggers periostin (Postn) expression in the periosteum and osteocytes (Oc), which downregulates Sost and activates β-catenin signaling. Hence the cortical bone response to loading is abolished in Postn−/− mice. Here we investigated the role of Oc β-catenin and its interaction with Postn on the bone biomechanical response. Postn−/− were bred with Oc-Ctnn−/− mice to generate Po...

Non-pharmacologic approaches to preserve or increase BMD include whole body vibration (WBV). A meta-analysis and one-year randomized trial concluded that WBV has no effect on BMD in older women; however, previous trials were relatively brief and did not include a sham control group. Therefore, we conducted the Vibration to Improve Bone in Elderly Subjects (‘VIBES’) trial, a randomized, sham-controlled trial of 10 min of daily WBV (0.3 g at 30 Hz) in seniors recruited...

Background: There are no models for estimating risk of fracture in patients taking treatments for osteoporosis. Knowing a patient’s risk of fracture during treatment may help make future treatment decisions; therefore, the development of on-treatment fracture risk models is needed.Methods: To assess on-treatment fracture risk, the analysis included subjects who received denosumab (DMAb) 60 mg Q6 every 6 months for at least 1 year in either FREEDOM o...

Introduction: Administration of antibodies that neutralize sclerostin has been demonstrated to increase bone mass. We report the key findings of a Phase 2 study of the human sclerostin antibody, blosozumab (bmab).Methods: Study GSDB was a randomized, parallel-design, double-blind placebo-controlled study, designed to assess the dose–response relationship of bmab in postmenopausal women with low bone mineral density (BMD; lumbar spine (LS) T...

Romosozumab is an investigational bone-forming agent that inhibits sclerostin. Recent data demonstrated that it stimulated bone formation, decreased bone resorption, and led to rapid and substantial increases in areal bone mineral density (BMD; McClung, J Bone Miner Res 27 (S1) S8–S9, 2012). In a Phase 1b, randomized, double-blind, placebo-controlled, multiple dose study, we studied the effects of romosozumab administered for 3 months and follow-...