BMP signaling is required for adult skeletal homeostasis and mediates bone anabolic action of parathyroid hormone |
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| Affiliation: | 1. Division of Endocrinology and Center for Research in Anabolic Skeletal Targets in Health and Illness (ASTHI), CSIR-Central Drug Research Institute, Sector 10 Jankipuram Extension, Sitapur Road, Lucknow 226031, India;2. Department of Biological Sciences and Bioengineering, Indian Institute of Technology Kanpur 208016, India;3. Division of Biochemistry, CSIR-Central Drug Research Institute, Sector 10 Jankipuram Extension, Sitapur Road, Lucknow 226031, India;4. AcSIR, CSIR-Central Drug Research Institute, Lucknow 226031, India;1. Division of Human Genetics, Children''s Hospital of Philadelphia, Philadelphia, USA;2. Department of Genetics, University of Pennsylvania, Philadelphia, USA;3. Division of Orthopedic Surgery, Children''s Hospital of Philadelphia, Perelman School of Medicine at University of Pennsylvania, USA;4. Department of Systems Pharmacology and Translation Therapeutics, University of Pennsylvania, Philadelphia, USA;5. Institute of Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia, USA;6. Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA;7. Division of Endocrinology and Diabetes, Children''s Hospital of Philadelphia, Philadelphia, USA;1. Department of Diabetes, Endocrinology and Nutrition, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawahara-cho, Sakyo-ku, 606-8507 Kyoto, Japan;2. Department of Maxillofacial Surgery, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawahara-cho, Sakyo-ku, 606-8507 Kyoto, Japan;1. Department of Biomedical Engineering, University of Wisconsin, Madison, WI, United States;2. Orthopedics & Rehabilitation, University of Wisconsin, Madison, WI, United States;3. Mechanical Engineering, University of Wisconsin, Madison, WI, United States;4. Laboratory for Optical and Computational Instrumentation, University of Wisconsin, Madison, WI, United States;5. American Family Children''s Hospital, University of Wisconsin, Madison, WI, United States;6. Department of Biomedical Engineering, Rensselaer Polytechnic Institute, Troy, NY, United States;7. Department of Radiology, Musculoskeletal Division, Johns Hopkins School of Medicine, Baltimore, MD, United States;1. Cluster for Craniofacial Development & Regeneration Research, Institute of Oral Biosciences (BK21 program) and School of Dentistry, Chonbuk National University, Jeonju 54896, South Korea;2. Department of Bioactive Material Sciences, Research Center of Bioactive Materials, Chonbuk National University, Jeonju 54896, South Korea;3. Chonnam National University Dental Hospital, Kwangju 61186, South Korea;4. School of Dentistry and Dental Research Institute, Seoul National University, Seoul 08826, South Korea;5. Research Institute of Biotechnology, Dongguk University, Seoul 04620, South Korea;1. INSERM U1132 BIOSCAR, Hôpital Lariboisière, 75010 Paris, France;2. University Paris Diderot, Sorbonne Paris Cité, Paris, France;3. Department of Endocrinology and Internal Medicine, THG, Aarhus University Hospital, DK-8000 Aarhus, Denmark;4. Department of Orthopaedic Surgery, Hôpital Lariboisière, AP-HP, 75010 Paris, France;5. Centre National de Genotypage, Institut Génomique, Commissariat à l''énergie Atomique, 2 rue Gaston Crémieux, CP5721 91057 Evry Cedex, France;6. Service de Rhumatologie, GH Saint-Louis Lariboisière Fernand Widal, 75010 Paris, France;1. Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN 27212, USA;2. Department of Orthopaedic Surgery & Rehabilitation, Vanderbilt University Medical Center, Nashville, TN 37232, USA;3. Center for Bone Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA;4. Department of Biomedical Engineering, Vanderbilt University, Nashville, TN 37232, USA;5. Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA;6. Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA;7. The Cancer Therapy & Research Center, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA;8. Department of Cancer Biology, Vanderbilt University, Nashville, TN 37232, USA |
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| Abstract: | Bmp2 and Bmp4 genes were ablated in adult mice (KO) using a conditional gene knockout technology. Bones were evaluated by microcomputed tomography (μCT), bone strength tester, histomorphometry and serum biochemical markers of bone turnover. Drill-hole was made at femur metaphysis and bone regeneration in the hole site was measured by calcein binding and μCT. Mice were either sham operated (ovary intact) or ovariectomized (OVX), and treated with human parathyroid hormone (PTH), 17β-estradiol (E2) or vehicle. KO mice displayed trabecular bone loss, diminished osteoid formation and reduced biomechanical strength compared with control (expressing Bmp2 and Bmp4). Both osteoblast and osteoclast functions were impaired in KO mice. Bone histomorphomtery and serum parameters established a low turnover bone loss in KO mice. Bone regeneration at the drill-hole site in KO mice was lower than control. However, deletion of Bmp2 gene alone had no effect on skeleton, an outcome similar to that reported previously for deletion of Bmp4 gene. Both PTH and E2 resulted in skeletal preservation in control-OVX, whereas in KO-OVX, E2 but not PTH was effective which suggested that the skeletal action of PTH required Bmp ligands but E2 did not. To determine cellular effects of Bmp2 and Bmp4, we used bone marrow stromal cells in which PTH but not E2 stimulated both Bmp2 and Bmp4 synthesis leading to increased Smad1/5 phosphorylation. Taken together, we conclude that Bmp2 and Bmp4 are essential for maintaining adult skeletal homeostasis and mediating the anabolic action of PTH. |
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