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      The Effect of Bovine Parathyroid Hormone Withdrawal on MC3T3-E1 Cell Proliferation and Phosphorus Metabolism

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          Abstract

          Hypocalcemia and hypophosphatemia are common complications after parathyroidectomy (PTX). Sudden removal of high circulating levels of parathyroid hormone (PTH) causes decreased osteoclastic resorption resulting in a decreased bone remodeling space. These phenomena are likely due to an increased influx of calcium and phosphorus into bone. However, there are currently no data to support this hypothesis. In this study, we found that PTX significantly reduced levels of PTH, calcium and phosphate. Compared with preoperative levels, after 1 year, postoperative PTH, calcium and phosphate levels were 295.6 ± 173.7 pg/mL (P < 0.05), 86.62 ± 15.98 mg/dL (P < 0.05) and 5.56 ± 2.03 mg/dL (P < 0.05), respectively. We investigated continuous bovine PTH administration as well as withdrawal of bovine PTH stimulation in the mouse osteoblast precursor cell line MC3T3-E1. MC3T3-E1 cells were cultured with continuous bovine PTH treatment for 20 days or with transient bovine PTH treatment for 10 days. High doses of continuous bovine PTH exposure strongly reduced cell proliferation, alkaline phosphatase activity and the number of mineralized calcium nodules. However, withdrawal of bovine PTH (100 ng/mL) significantly increased the number of mineralized calcium nodules and caused a rapid decline in calcium and phosphorus content of culture medium. In conclusion, continuous exposure to bovine PTH inhibited osteoblast differentiation and reduced the formation of mineralized nodules. However, this inhibition was removed and mineralized nodule formation resumed with withdrawal of bovine PTH. According to the results of our clinical examinations and in vitro experiments, we hypothesize that the sudden removal of high levels of PTH may cause an increased influx of calcium and phosphorus into bone after PTX.

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          Osteonal and hemi-osteonal remodeling: the spatial and temporal framework for signal traffic in adult human bone.

          D Parfitt (1994)
          The bone replacement process in the adult skeleton is known as remodeling. When bone is removed by osteoclasts, new bone is laid down by osteoblasts in the same place, because the load bearing requirement is unchanged. Bone is usually replaced because it is too old to carry out its function, which is mainly mechanical in cortical bone and mainly support for homeostasis and hematopoiesis in cancellous bone. Remodeling always begins on a quiescent bone surface, separated from the marrow by flat lining cells that are one of the two modes of terminal differentiation of osteoblasts. Lining cells are gatekeepers, able to be informed of the need for remodeling, and to either execute or mediate all four components of its activation-selection and preparation of the site, recruitment of mononuclear preosteoclasts, budding of new capillaries, and attraction of preosteoclasts to the chosen site where they fuse into multinucleated osteoclasts. In cortical bone, osteonal remodeling is carried out by a complex and unique structure, the basic multicellular unit (BMU) that comprises a cutting cone of osteoclasts in front, a closing cone lined by osteoblasts following behind, and connective tissue, blood vessels and nerves filling the cavity. The BMU maintains its size, shape and internal organization for many months as it travels through bone in a controlled direction. Individual osteoclast nuclei are short-lived, turning over about 8% per d, replaced by new preosteoclasts that originated in the bone marrow and travel in the circulation to the site of resorption. Refilling of bone at each successive cross-sectional location is accomplished by a team of osteoblasts, probably originating from precursors within the local connective tissue, all assembled within a narrow window of time, at the right location, and in the right orientation to the surface. Each osteoblast team forms bone most rapidly at its onset and slows down progressively. Some of the osteoblasts are buried as osteocytes, some die, and the remainder gradually assume the shape of lining cells. Cancellous bone is more accessible to study than cortical bone, but is geometrically complex. Although remodeling conforms to the same sequence of surface activation, resorption and formation, its three-dimensional organization is difficult to visualize from two-dimensional histologic sections.(ABSTRACT TRUNCATED AT 400 WORDS)
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            Molecular and cellular mechanisms of the anabolic effect of intermittent PTH.

            Robert L. Jilka (2007)
            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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              Hungry bone syndrome: still a challenge in the post-operative management of primary hyperparathyroidism: a systematic review of the literature.

              J E Witteveen, Bibi S. van Thiel, J. Romijn … (2013)
              Hungry bone syndrome (HBS) refers to the rapid, profound, and prolonged hypocalcaemia associated with hypophosphataemia and hypomagnesaemia, and is exacerbated by suppressed parathyroid hormone (PTH) levels, which follows parathyroidectomy in patients with severe primary hyperparathyroidism (PHPT) and preoperative high bone turnover. It is a relatively uncommon, but serious adverse effect of parathyroidectomy. We conducted a literature search of all available studies reporting a 'hungry bone syndrome' in patients who had a parathyroidectomy for PHPT, to identify patients at risk and address the pitfalls in their management. The severe hypocalcaemia is believed to be due to increased influx of calcium into bone, due to the sudden removal of the effect of high circulating levels of PTH on osteoclastic resorption, leading to a decrease in the activation frequency of new remodelling sites and to a decrease in remodelling space, although there is no good documentation for this. Various risk factors have been suggested for the development of HBS, including older age, weight/volume of the resected parathyroid glands, radiological evidence of bone disease and vitamin D deficiency. The syndrome is reported in 25-90% of patients with radiological evidence of hyperparathyroid bone disease vs only 0-6% of patients without skeletal involvement. There is insufficient data-based evidence on the best means to treat, minimise or prevent this severe complication of parathyroidectomy. Treatment is aimed at replenishing the severe calcium deficit by using high doses of calcium supplemented by high doses of active metabolites of vitamin D. Adequate correction of magnesium deficiency and normalisation of bone turnover are required for resolution of the hypocalcaemia which may last for a number of months after successful surgery. Preoperative treatment with bisphosphonates has been suggested to reduce post-operative hypocalcaemia, but there are to date no prospective studies addressing this issue.
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                Author and article information

                Contributors
                Andre van Wijnen: Role: Academic Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (iso-abbrev): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, CA USA )
                ISSN (Electronic): 1932-6203
                Publication date (Electronic): 16 March 2015
                Publication date Collection: 2015
                Volume: 10
                Issue: 3
                Electronic Location Identifier: e0120402
                Affiliations
                [1 ]Department of Nephrology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, 106 Zhongshan No. 2 Road, Guangzhou, China
                [2 ]Department of Nephrology, the Fifth Affiliated Hospital of Sun Yat-sen University, No.52 Meihua Road, Zhuhai, China
                University of Massachusetts Medical, UNITED STATES
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: S. Liu WZ. Performed the experiments: WZ S. Li. Analyzed the data: TC Zhonghe Li. Contributed reagents/materials/analysis tools: WS. Wrote the paper: WZ. Contributed part of the clinical study: BZ Zhuo Li JW XL Z. Lin. Contributed an edit of this manuscript: WS.

                Article
                Publisher ID: PONE-D-14-31312
                DOI: 10.1371/journal.pone.0120402
                PMC ID: 4361577
                PubMed ID: 25775025
                SO-VID: e1776d36-5457-43fa-9881-cc1dad423cc2
                Copyright statement: Copyright @ 2015
                License:

                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
                Date received : 13 July 2014
                Date accepted : 25 January 2015
                Page count
                Figures: 5, Tables: 2, Pages: 12
                Funding
                This work was supported by Guangdong Provincial Science and Technology Foundation (No. 2012B031800164 and 2011B031800303), the National Natural Science Foundation (No. 81370808, 81270784 and 81170683), Guangzhou City Science and Technology Project (No. 12A56041537, 2012J4300084 and 2012Y2-00028), National Key Technology R&D Program (No. 2011BAI10B06), National key clinical specialist construction Programs of China, Chinese Society of Nephrology (No.14050400577) and Medical Scientific Research Foundation of Guangdong Province (No.A2014259). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Subject: Research Article
                Custom metadata
                Data Availability All relevant data are within the paper.

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