title: BMP signaling is required for adult skeletal homeostasis and mediates bone anabolic action of parathyroid hormone.
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.
authors: 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.
authors: Mohd Parvez
authors: MP
authors: Khan
authors: 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.
authors: Kainat
authors: K
authors: Khan
authors: Department of Biological Sciences and Bioengineering, Indian Institute of Technology Kanpur 208016, India.
authors: Prem Swaroop
authors: PS
authors: Yadav
authors: Division of Biochemistry, CSIR-Central Drug Research Institute, Sector 10 Jankipuram Extension, Sitapur Road, Lucknow 226031, India.
authors: Abhishek Kumar
authors: AK
authors: Singh
authors: Department of Biological Sciences and Bioengineering, Indian Institute of Technology Kanpur 208016, India.
authors: Aditi
authors: A
authors: Nag
authors: Department of Biological Sciences and Bioengineering, Indian Institute of Technology Kanpur 208016, India.
authors: Paritosh
authors: P
authors: Prasahar
authors: 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; AcSIR, CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors: Monika
authors: M
authors: Mittal
authors: 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; AcSIR, CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors: Shyamsundar Pal
authors: SP
authors: China
authors: 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.
authors: Mahesh Chandra
authors: MC
authors: Tewari
authors: 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.
authors: Geet Kumar
authors: GK
authors: Nagar
authors: 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.
authors: Deepshikha
authors: D
authors: Tewari
authors: Division of Biochemistry, CSIR-Central Drug Research Institute, Sector 10 Jankipuram Extension, Sitapur Road, Lucknow 226031, India.
authors: Arun Kumar
authors: AK
authors: Trivedi
authors: Division of Biochemistry, CSIR-Central Drug Research Institute, Sector 10 Jankipuram Extension, Sitapur Road, Lucknow 226031, India.
authors: Sabyasachi
authors: S
authors: Sanyal
authors: Department of Biological Sciences and Bioengineering, Indian Institute of Technology Kanpur 208016, India. Electronic address: abandopa@iitk.ac.in.
authors: Amitabha
authors: A
authors: Bandyopadhyay
authors: 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; AcSIR, CSIR-Central Drug Research Institute, Lucknow 226031, India. Electronic address: n_chattopadhyay@cdri.res.in.
authors: Naibedya
authors: N
authors: Chattopadhyay
mesh_terms: D045930:Anabolic Agents / Q000494:pharmacology; D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000502:physiology*; D055415:Bone Morphogenetic Protein 4 / Q000502:physiology*; D016723:Bone Remodeling / Q000187:drug effects / Q000502:physiology*; D005260:Female; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D010281:Parathyroid Hormone / Q000494:pharmacology*; D011897:Random Allocation; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
chemical_list: D045930:Anabolic Agents; C525718:BMP2 protein, human; C525809:BMP4 protein, human; D055396:Bone Morphogenetic Protein 2; D055415:Bone Morphogenetic Protein 4; C470125:PTH protein, human; D010281:Parathyroid Hormone
keywords: Bone; Bone morphogenetic protein (BMP); Estrogen; Osteoblast; Parathyroid hormone