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      Dissociation of Bone Resorption and Bone Formation in Adult Mice with a Non-Functional V-ATPase in Osteoclasts Leads to Increased Bone Strength

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          Abstract

          Osteopetrosis caused by defective acid secretion by the osteoclast, is characterized by defective bone resorption, increased osteoclast numbers, while bone formation is normal or increased. In contrast the bones are of poor quality, despite this uncoupling of formation from resorption.

          To shed light on the effect of uncoupling in adult mice with respect to bone strength, we transplanted irradiated three-month old normal mice with hematopoietic stem cells from control or oc/oc mice, which have defective acid secretion, and followed them for 12 to 28 weeks.

          Engraftment levels were assessed by flow cytometry of peripheral blood. Serum samples were collected every six weeks for measurement of bone turnover markers. At termination bones were collected for µCT and mechanical testing.

          An engraftment level of 98% was obtained. From week 6 until termination bone resorption was significantly reduced, while the osteoclast number was increased when comparing oc/oc to controls. Bone formation was elevated at week 6, normalized at week 12, and reduced onwards. µCT and mechanical analyses of femurs and vertebrae showed increased bone volume and bone strength of cortical and trabecular bone.

          In conclusion, these data show that attenuation of acid secretion in adult mice leads to uncoupling and improves bone strength.

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          Most cited references67

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          Bone histomorphometry: standardization of nomenclature, symbols, and units. Report of the ASBMR Histomorphometry Nomenclature Committee.

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            RANK is the intrinsic hematopoietic cell surface receptor that controls osteoclastogenesis and regulation of bone mass and calcium metabolism.

            We have generated RANK (receptor activator of NF-kappaB) nullizygous mice to determine the molecular genetic interactions between osteoprotegerin, osteoprotegerin ligand, and RANK during bone resorption and remodeling processes. RANK(-/-) mice lack osteoclasts and have a profound defect in bone resorption and remodeling and in the development of the cartilaginous growth plates of endochondral bone. The osteopetrosis observed in these mice can be reversed by transplantation of bone marrow from rag1(-/-) (recombinase activating gene 1) mice, indicating that RANK(-/-) mice have an intrinsic defect in osteoclast function. Calciotropic hormones and proresorptive cytokines that are known to induce bone resorption in mice and human were administered to RANK(-/-) mice without inducing hypercalcemia, although tumor necrosis factor alpha treatment leads to the rare appearance of osteoclast-like cells near the site of injection. Osteoclastogenesis can be initiated in RANK(-/-) mice by transfer of the RANK cDNA back into hematopoietic precursors, suggesting a means to critically evaluate RANK structural features required for bone resorption. Together these data indicate that RANK is the intrinsic cell surface determinant that mediates osteoprotegerin ligand effects on bone resorption and remodeling as well as the physiological and pathological effects of calciotropic hormones and proresorptive cytokines.
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              Bidirectional ephrinB2-EphB4 signaling controls bone homeostasis.

              Bone homeostasis requires a delicate balance between the activities of bone-resorbing osteoclasts and bone-forming osteoblasts. Various molecules coordinate osteoclast function with that of osteoblasts; however, molecules that mediate osteoclast-osteoblast interactions by simultaneous signal transduction in both cell types have not yet been identified. Here we show that osteoclasts express the NFATc1 target gene Efnb2 (encoding ephrinB2), while osteoblasts express the receptor EphB4, along with other ephrin-Eph family members. Using gain- and loss-of-function experiments, we demonstrate that reverse signaling through ephrinB2 into osteoclast precursors suppresses osteoclast differentiation by inhibiting the osteoclastogenic c-Fos-NFATc1 cascade. In addition, forward signaling through EphB4 into osteoblasts enhances osteogenic differentiation, and overexpression of EphB4 in osteoblasts increases bone mass in transgenic mice. These data demonstrate that ephrin-Eph bidirectional signaling links two major molecular mechanisms for cell differentiation--one in osteoclasts and the other in osteoblasts--thereby maintaining bone homeostasis.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2011
                7 November 2011
                : 6
                : 11
                : e27482
                Affiliations
                [1 ]Nordic Bioscience A/S, Herlev, Denmark
                [2 ]Molecular Medicine and Gene Therapy, Lund University, Lund, Sweden
                [3 ]Institute of Anatomy, University of Aarhus, Aarhus, Denmark
                [4 ]Department of Functional Anatomy, Academic Centre of Dentistry Amsterdam (ACTA), University of Amsterdam and VU University Amsterdam, Research Institute MOVE, Amsterdam, The Netherlands
                [5 ]St. Vincent's Institute for Medical Research, Melbourne, Australia
                [6 ]Department of Oral Cell Biology, Academic Centre of Dentistry Amsterdam (ACTA), University of Amsterdam and VU University Amsterdam Research Institute MOVE, Amsterdam, The Netherlands
                Florida International University, United States of America
                Author notes

                Conceived and designed the experiments: KH CF MAK JR. Performed the experiments: CF JST AMB CST AVNW GEJL NS MA. Analyzed the data: KH JST AMB CF GEJL VE NS TJM MAK JR. Wrote the paper: KH JR. Read, commented and approved the final version of the manuscript: KM CF JST AMB CST AVNW GEJL NS MA TJM VE MAK JR.

                Article
                PONE-D-11-10499
                10.1371/journal.pone.0027482
                3210177
                22087326
                e43b1918-19d3-4e86-b735-6fb7e4ec504a
                Henriksen et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                : 7 June 2011
                : 17 October 2011
                Page count
                Pages: 11
                Categories
                Research Article
                Biology
                Anatomy and Physiology
                Musculoskeletal System
                Biomechanics
                Bone and Joint Mechanics
                Bone
                Cell Physiology
                Endocrine System
                Histology
                Model Organisms
                Animal Models
                Mouse
                Molecular Cell Biology
                Cellular Types
                Bone Marrow Cells
                Cytometry
                Flow Cytometry
                Systems Biology
                Medicine
                Anatomy and Physiology
                Musculoskeletal System
                Biomechanics
                Bone and Joint Mechanics
                Bone
                Oncology
                Cancers and Neoplasms
                Bone and Soft Tissue Sarcomas
                Osteoblastoma
                Rheumatology
                Bone and Mineral Metabolism
                Women's Health
                Osteopenia and Osteoporosis

                Uncategorized
                Uncategorized

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