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      Short-term intermittent administration of parathyroid hormone facilitates osteogenesis by different mechanisms in cancellous and cortical bone

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          Abstract

          Intermittent administration of human parathyroid hormone (1–34)[hPTH(1–34)] induces anabolic action on the bones. To understand the mechanism underlying the early phase of hPTH(1–34)-induced anabolic action, we investigated the expression profiles of osterix and sclerostin after short-term intermittent administration of hPTH(1–34) using immunohistochemistry in adult rats. In the cancellous bone, hPTH(1–34) administration greatly increased the number of osterix-positive cells in the bone marrow on day 1, but the cells gradually decreased on days 3 and 5. Injections of hPTH(1–34) induced no significant changes in the number of sclerostin-positive osteocytes in the cancellous bone. In the cortical bone, intermittent administration of hPTH(1–34) significantly reduced the number of sclerostin-positive osteocytes. The serum sclerostin level was downregulated and the osteocalcin level was upregulated on day 5 after intermittent administration of hPTH(1–34). Intermittent hPTH(1–34) injections increased osteoblast surface, osteoid thickness, and osteoid surface in cancellous bone, but not in cortical bone. This study suggested that the increase in osterix-positive osteoprogenitors in cancellous bone and the decrease in sclerostin-positive osteocytes in cortical bone play important roles in anabolic action on osteogenesis induced by short-term administration of hPTH(1–34).

          Highlights

          • We analyzed the effects of hPTH(1–34) injection into rats at early phase.

          • hPTH(1–34) injection increased the osterix-positive cells in bone marrow.

          • hPTH(1–34) injection decreased sclerostin-positive cells in cortical bone.

          • hPTH(1–34) exerts different effects in cancellous and cortical bone.

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          Most cited references26

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

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            Parathyroid hormone: anabolic and catabolic actions on the skeleton.

            Parathyroid hormone (PTH) is essential for the maintenance of calcium homeostasis through, in part, its actions to regulate bone remodeling. While PTH stimulates both bone formation and bone resorption, the duration and periodicity of exposure to PTH governs the net effect on bone mass, that is whether it is catabolic or anabolic. PTH receptor signaling in osteoblasts and osteocytes can increase the RANKL/OPG ratio, increasing both osteoclast recruitment and osteoclast activity, and thereby stimulating bone resorption. In contrast, PTH-induced bone formation is explained, at least in part, by its ability to downregulate SOST/sclerostin expression in osteocytes, permitting the anabolic Wnt signaling pathway to proceed. The two modes of administration of PTH, that is, continuous vs. intermittent, can regulate, in bone cells, different sets of genes; alternatively, the same sets of genes exposed to PTH in sustained vs. transient way, will favor bone resorption or bone formation, respectively. This article reviews the effects of PTH on bone cells that lead to these dual catabolic and anabolic actions on the skeleton.
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              Molecular and cellular mechanisms of the anabolic effect of intermittent PTH.

              Intermittent administration of parathyroid hormone (PTH) stimulates bone formation by increasing osteoblast number, but the molecular and cellular mechanisms underlying this effect are not completely understood. In vitro and in vivo studies have shown that PTH directly activates survival signaling in osteoblasts; and that delay of osteoblast apoptosis is a major contributor to the increased osteoblast number, at least in mice. This effect requires Runx2-dependent expression of anti-apoptotic genes like Bcl-2. PTH also causes exit of replicating progenitors from the cell cycle by decreasing expression of cyclin D and increasing expression of several cyclin-dependent kinase inhibitors. Exit from the cell cycle may set the stage for pro-differentiating and pro-survival effects of locally produced growth factors and cytokines, the level and/or activity of which are known to be influenced by PTH. Observations from genetically modified mice suggest that the anabolic effect of intermittent PTH requires insulin-like growth factor-I (IGF-I), fibroblast growth factor-2 (FGF-2), and perhaps Wnts. Attenuation of the negative effects of PPAR gamma may also lead to increased osteoblast number. Daily injections of PTH may add to the pro-differentiating and pro-survival effects of locally produced PTH related protein (PTHrP). As a result, osteoblast number increases beyond that needed to replace the bone removed by osteoclasts during bone remodeling. The pleiotropic effects of intermittent PTH, each of which alone may increase osteoblast number, may explain why this therapy reverses bone loss in most osteoporotic individuals regardless of the underlying pathophysiology.
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                Author and article information

                Contributors
                Journal
                Bone Rep
                Bone Rep
                Bone Reports
                Elsevier
                2352-1872
                16 January 2016
                December 2016
                16 January 2016
                : 5
                : 7-14
                Affiliations
                [a ]Department of Oral Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8549, Japan
                [b ]Department of Maxillofacial Orthognathics, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8549, Japan
                [c ]Division of Bio-Imaging, Proteo-Science Center (PROS), Ehime University, Ehime 791-0295, Japan
                [d ]Department of Orthopedics, Juntendo Tokyo Koto Geriatric Medical Center, Tokyo 136-0075, Japan
                [e ]Pharmaceuticals Research Center, Asahi Kasei Pharma Corporation, 632-1 Mifuku, Izunokuni, Shizuoka 410-2321, Japan
                [f ]Oral Health Science Center, Tokyo Dental College, Tokyo 101-0061, Japan
                Author notes
                [* ]Corresponding author at: Oral Health Science Center, Tokyo Dental College, Tokyo 101-0061, Japan.Oral Health Science CenterTokyo Dental CollegeTokyo101-0061Japan akira@ 123456tdc.ac.jp
                Article
                S2352-1872(16)30002-X
                10.1016/j.bonr.2016.01.002
                4926844
                6ff9bd7f-fc09-42dc-a7e6-f3581bd59b23
                © 2016 The Authors

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 17 November 2015
                : 25 December 2015
                : 15 January 2016
                Categories
                Article

                pth,osteogenesis,osterix,sclerostin,cortical bone,cancellous bone

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