Women's Health and Musculoskeletal Biology, Wyeth Research, 500 Arcola Road, Collegeville, PA 19426, USA.
Published: June 2009
AI Article Synopsis
Article Abstract
Canonical Wnt signaling has been demonstrated to increase bone formation, and Wnt pathway components are being pursued as potential drug targets for osteoporosis and other metabolic bone diseases. Deletion of the Wnt antagonist secreted frizzled-related protein (sFRP)-1 in mice activates canonical signaling in bone and increases trabecular bone formation in aged animals. We have developed small molecules that bind to and inhibit sFRP-1 in vitro and demonstrate robust anabolic activity in an ex vivo organ culture assay. A library of over 440,000 drug-like compounds was screened for inhibitors of human sFRP-1 using a cell-based functional assay that measured activation of canonical Wnt signaling with an optimized T-cell factor (TCF)-luciferase reporter gene assay. One of the hits in this screen, a diarylsulfone sulfonamide, bound to sFRP-1 with a K(D) of 0.35 microM in a tryptophan fluorescence quenching assay. This compound also selectively inhibited sFRP-1 with an EC(50) of 3.9 microM in the cell-based functional assay. Optimization of this high throughput screening hit for binding and functional potency as well as metabolic stability and other pharmaceutical properties led to improved lead compounds. One of these leads (WAY-316606) bound to sFRP-1 with a K(D) of 0.08 microM and inhibited it with an EC(50) of 0.65 microM. Moreover, this compound increased total bone area in a murine calvarial organ culture assay at concentrations as low as 0.0001 microM. This work demonstrates the feasibility of developing small molecules that inhibit sFRP-1 and stimulate canonical Wnt signaling to increase bone formation.
Department of Cardiovascular Surgery, Centro Cardiologico Monzino IRCCS, 20138 Milan, Italy; Department of Biomedical, Surgical, and Dental Sciences, University of Milan, 20122 Milan, Italy.
Aim: Percutaneous vertebroplasty is generally considered a safe procedure, however, cases of cardioembolism and cardiac perforation have been reported.
Case Presentation: A 69-year-old woman was referred to our emergency department after an outpatient echocardiogram revealed a "thrombus-like" formation involving the right heart. Two weeks before she had undergone percutaneous vertebroplasty of the third to fifth lumbar vertebrae due to osteoporotic fractures.
Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi'an Jiaotong University, Xi'an, Shaanxi, China.
Introduction: Alveolar bone defects pose significant challenges in dentistry. Due to the complexity of alveolar bone anatomy and insufficient repair mechanisms, large bone defects are difficult for the body to heal naturally. Clinical treatment typically involves the use of bone substitute materials.
Bone sialoprotein (Ibsp/BSP) is a bone-associated extracellular matrix protein. Ibsp knockout (Ibsp) mice exhibit defective alveolar bone formation, mineralization, and healing. We hypothesized BSP would rescue defective alveolar bone healing in a molar extraction model in Ibsp mice.
Center of Excellence for Dental Stem Cell Biology, Faculty of Dentistry, Chulalongkorn University, Bangkok, Thailand; Department of Anatomy, Faculty of Dentistry, Chulalongkorn University, Bangkok, Thailand. Electronic address:
Objectives: Periodontal ligament stem cells (PDLSCs) are promising for regenerative therapies due to their self-renewal and multilineage differentiation, essential for periodontal tissue repair. Although magnesium plays a vital role in bone metabolism, its specific effects on PDLSCs and potential applications in regeneration are unclear. This study aimed to investigate the effects of magnesium chloride (MgCl₂) on the proliferation and osteogenic differentiation of human PDLSCs (hPDLSCs).
