The calcitonin receptor regulates osteocyte lacunae acidity during lactation in mice

in Journal of Endocrinology
Authors:
Rachel A Davey Department of Medicine, Austin Health, University of Melbourne, Heidelberg, Victoria, Australia

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Michele V Clarke Department of Medicine, Austin Health, University of Melbourne, Heidelberg, Victoria, Australia

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Suzanne B Golub Department of Medicine, Austin Health, University of Melbourne, Heidelberg, Victoria, Australia

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Patricia K Russell Department of Medicine, Austin Health, University of Melbourne, Heidelberg, Victoria, Australia

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Jeffrey D Zajac Department of Medicine, Austin Health, University of Melbourne, Heidelberg, Victoria, Australia

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Correspondence should be addressed to R A Davey: r.davey@unimelb.edu.au
DOI:
https://doi.org/10.1530/JOE-20-0599
Volume/Issue:
Volume 249: Issue 1
Article Type:
Research Article
Page Range:
31–41
Online Publication Date:
Apr 2021
Copyright:
© 2021 Society for Endocrinology 2021
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The physiological role of calcitonin, and its receptor, the CTR (or Calcr), has long been debated. We previously provided the first evidence for a physiological role of the CTR to limit maternal bone loss during lactation in mice by a direct action on osteocytes to inhibit osteocytic osteolysis. We now extend these findings to show that CTR gene expression is upregulated two- to three-fold in whole bone of control mice at the end of pregnancy (E18) and lactation (P21) compared to virgin controls. This was associated with an increase in osteoclast activity evidenced by increases in osteoclast surface/bone surface and Dcstamp gene expression. To investigate the mechanism by which the CTR inhibits osteocytic osteolysis, in vivo acidification of the osteocyte lacunae during lactation (P14 days) was assessed using a pH indicator dye. A lower pH was observed in the osteocyte lacunae of lactating Global-CTRKOs compared to controls and was associated with an increase in the gene expression of ATPase H+ transporting V0 subunit D2 (Atp6v0d2) in whole bone of Global-CTRKOs at the end of lacation (P21). To determine whether the CTR is required for the replacement of mineral within the lacunae post-lactation, lacunar area was determined 3 weeks post-weaning. Comparison of the largest 20% of lacunae by area did not differ between Global-CTRKOs and controls post-lactation. These results provide evidence for CTR activation to inhibit osteocytic osteolysis during lactation being mediated by regulating the acidity of the lacunae microenvironment, whilst the CTR is dispensable for replacement of bone mineral within lacunae by osteocytes post-lactation.

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Print ISSN:
0022-0795
Online ISSN:
1479-6805
Copyright:
© 2021 Society for Endocrinology 2021
Page(s):
11
Article Type:
Research Article
Received Date:
01 Feb 2021
Accepted Date:
23 Feb 2021
Print Publication Date:
01 Apr 2021
Online Publication Date:
Apr 2021
Keywords:
calcitonin receptor; bone; lactation; osteocytes; osteolysis

  • Ardeshirpour L, Dann P, Adams DJ, Nelson T, VanHouten J, Horowitz MC & Wysolmerski JJ 2007 Weaning triggers a decrease in receptor activator of nuclear factor-kappaB ligand expression, widespread osteoclast apoptosis, and rapid recovery of bone mass after lactation in mice. Endocrinology 148 3875–3886. (https://doi.org/10.1210/en.2006-1467)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Atkins GJ & Findlay DM 2012 Osteocyte regulation of bone mineral: a little give and take. Osteoporosis International 23 2067–2079. (https://doi.org/10.1007/s00198-012-1915-z)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Bjornerem Å, Ghasem-Zadeh A, Wang X, Bui M, Walker SP, Zebaze R & Seeman E 2017 Irreversible deterioration of cortical and trabecular microstructure associated with breastfeeding. Journal of Bone and Mineral Research 32 681–687. (https://doi.org/10.1002/jbmr.3018)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Bucht E, Telenius-Berg M, Lundell G & Sjoberg HE 1986 Immunoextracted calcitonin in milk and plasma from totally thyroidectomized women. Evidence of monomeric calcitonin in plasma during pregnancy and lactation. Acta Endocrinologica 113 529–535. (https://doi.org/10.1530/acta.0.1130529)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Chia LY, Walsh NC, Martin TJ & Sims NA 2015 Isolation and gene expression of haematopoietic-cell-free preparations of highly purified murine osteocytes. Bone 72 34–42. (https://doi.org/10.1016/j.bone.2014.11.005)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Clarke MV, Russell PK, Findlay DM, Sastra S, Anderson PH, Skinner JP, Atkins GJ, Zajac JD & Davey RA 2015 A role for the calcitonin receptor to limit bone loss during lactation in female mice by inhibiting osteocytic osteolysis. Endocrinology 156 3203–3214. (https://doi.org/10.1210/en.2015-1345)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Cooper CW, Hirsch PF, Toverud SU & Munson PL 1967 An improved method for the biological assay of thyrocalcitonin. Endocrinology 81 610–616. (https://doi.org/10.1210/endo-81-3-610)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Davey RA, Hahn CN, May BK & Morris HA 2000 Osteoblast gene expression in rat long bones: effects of ovariectomy and dihydrotestosterone on mRNA levels. Calcified Tissue International 67 75–79. (https://doi.org/10.1007/s00223001100)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Davey RA, Turner AG, McManus JF, Chiu WS, Tjahyono F, Moore AJ, Atkins GJ, Anderson PH, Ma C & Glatt V et al.2008 Calcitonin receptor plays a physiological role to protect against hypercalcemia in mice. Journal of Bone and Mineral Research 23 1182–1193. (https://doi.org/10.1359/jbmr.080310)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Gonen E, Sahin I, Ozbek M, Kovalak E, Yologlu S & Ates Y 2005 Effects of pregnancy and lactation on bone mineral density, and their relation to the serum calcium, phosphorus, calcitonin and parathyroid hormone levels in rats. Journal of Endocrinological Investigation 28 322–326. (https://doi.org/10.1007/BF03347197)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Gooi JH, Pompolo S, Karsdal MA, Kulkarni NH, Kalajzic I, McAhren SH, Han B, Onyia JE, Ho PW & Gillespie MT et al.2010 Calcitonin impairs the anabolic effect of PTH in young rats and stimulates expression of sclerostin by osteocytes. Bone 46 1486–1497. (https://doi.org/10.1016/j.bone.2010.02.018)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Hattersley G & Chambers TJ 1989 Calcitonin receptors as markers for osteoclastic differentiation: correlation between generation of bone-resorptive cells and cells that express calcitonin receptors in mouse bone marrow cultures. Endocrinology 125 1606–1612. (https://doi.org/10.1210/endo-125-3-1606)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Hay DL & Pioszak AA 2016 Receptor activity-modifying proteins (RAMPs): new insights and roles. Annual Review of Pharmacology and Toxicology 56 469–487. (https://doi.org/10.1146/annurev-pharmtox-010715-103120)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Ishii A, Nakamura M, Nakamura A, Takeda K, Han B & Kakudo K 2006 Expression of calcitonin receptor in rat mammary gland during lactation. Endocrine Journal 53 317–324. (https://doi.org/10.1507/endocrj.k05-131)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Jahn K, Kelkar S, Zhao H, Xie Y, Tiede-Lewis LM, Dusevich V, Dallas SL & Bonewald LF 2017 Osteocytes acidify their microenvironment in response to PTHrP in vitro and in lactating mice in vivo. Journal of Bone and Mineral Research 32 1761–1772. (https://doi.org/10.1002/jbmr.3167)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Kogawa M, Wijenayaka AR, Ormsby RT, Thomas GP, Anderson PH, Bonewald LF, Findlay DM & Atkins GJ 2013 Sclerostin regulates release of bone mineral by osteocytes by induction of carbonic anhydrase 2. Journal of Bone and Mineral Research 28 2436–2448. (https://doi.org/10.1002/jbmr.2003)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Kouadjo KE, Nishida Y, Cadrin-Girard JF, Yoshioka M & St-Amand J 2007 Housekeeping and tissue-specific genes in mouse tissues. BMC Genomics 8 127. (https://doi.org/10.1186/1471-2164-8-127)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Kovacs CS 2005 Calcium and bone metabolism during pregnancy and lactation. Journal of Mammary Gland Biology and Neoplasia 10 105–118. (https://doi.org/10.1007/s10911-005-5394-0)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Kovacs CS 2016 Maternal mineral and bone metabolism during pregnancy, lactation, and post-weaning recovery. Physiological Reviews 96 449–547. (https://doi.org/10.1152/physrev.00027.2015)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Kovacs CS & Kronenberg HM 1997 Maternal-fetal calcium and bone metabolism during pregnancy, puerperium, and lactation. Endocrine Reviews 18 832–872. (https://doi.org/10.1210/edrv.18.6.0319)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Kukita T, Wada N, Kukita A, Kakimoto T, Sandra F, Toh K, Nagata K, Iijima T, Horiuchi M & Matsusaki H et al.2004 RANKL-induced DC-STAMP is essential for osteoclastogenesis. Journal of Experimental Medicine 200 941–946. (https://doi.org/10.1084/jem.20040518)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Lane NE, Yao W, Balooch M, Nalla RK, Balooch G, Habelitz S, Kinney JH & Bonewald LF 2006 Glucocorticoid-treated mice have localized changes in trabecular bone material properties and osteocyte lacunar size that are not observed in placebo-treated or estrogen-deficient mice. Journal of Bone and Mineral Research 21 466–476. (https://doi.org/10.1359/JBMR.051103)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Lin HY, Harris TL, Flannery MS, Aruffo A, Kaji EH, Gorn A, Kolakowski Jr LF, Lodish HF & Goldring SR 1991 Expression cloning of an adenylate cyclase-coupled calcitonin receptor. Science 254 1022–1024. (https://doi.org/10.1126/science.1658940)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Liu XS, Ardeshirpour L, VanHouten JN, Shane E & Wysolmerski JJ 2012 Site-specific changes in bone microarchitecture, mineralization, and stiffness during lactation and after weaning in mice. Journal of Bone and Mineral Research 27 865–875. (https://doi.org/10.1002/jbmr.1503)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Lotinun S, Ishihara Y, Nagano K, Kiviranta R, Carpentier VT, Neff L, Parkman V, Ide N, Hu D & Dann P et al.2019 Cathepsin K-deficient osteocytes prevent lactation-induced bone loss and parathyroid hormone suppression. Journal of Clinical Investigation 129 3058–3071. (https://doi.org/10.1172/JCI122936)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Martin TJ, Sexton PM & Findlay DM 2010 Calcitonin. In Endocrinology, 6th ed., pp. 1074–1088. Eds Jameson JL, De Groot LJElsevier Saunders Press.

  • Miller S 2006 Calcitonin – guardian of the Mammalian skeleton or is it just a fish story? Endocrinology 147 4007–4009. (https://doi.org/10.1210/en.2006-0599)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Miller SC & Bowman BM 2007 Rapid inactivation and apoptosis of osteoclasts in the maternal skeleton during the bone remodeling reversal at the end of lactation. Anatomical Record 290 65–73. (https://doi.org/10.1002/ar.20403)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Ota K, Quint P, Ruan M, Pederson L, Westendorf JJ, Khosla S & Oursler MJ 2013 Sclerostin is expressed in osteoclasts from aged mice and reduces osteoclast-mediated stimulation of mineralization. Journal of Cellular Biochemistry 114 1901–1907. (https://doi.org/10.1002/jcb.24537)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Powell Jr WF, Barry KJ, Tulum I, Kobayashi T, Harris SE, Bringhurst FR & Pajevic PD 2011 Targeted ablation of the PTH/PTHrP receptor in osteocytes impairs bone structure and homeostatic calcemic responses. Journal of Endocrinology 209 21–32. (https://doi.org/10.1530/JOE-10-0308)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Qing H, Ardeshirpour L, Pajevic PD, Dusevich V, Jahn K, Kato S, Wysolmerski J & Bonewald LF 2012 Demonstration of osteocytic perilacunar/canalicular remodeling in mice during lactation. Journal of Bone and Mineral Research 27 1018–1029. (https://doi.org/10.1002/jbmr.1567)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Schwenk F, Baron U & Rajewsky K 1995 A cre-transgenic mouse strain for the ubiquitous deletion of loxP-flanked gene segments including deletion in germ cells. Nucleic Acids Research 23 5080–5081. (https://doi.org/10.1093/nar/23.24.5080)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Sebastian A & Loots GG 2017 Transcriptional control of Sost in bone. Bone 96 76–84. (https://doi.org/10.1016/j.bone.2016.10.009)

  • Sexton PM 1991 Central nervous system binding sites for calcitonin and calcitonin gene-related peptide. Molecular Neurobiology 5 251–273. (https://doi.org/10.1007/BF02935550)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Singer FR, Aldred JP, Neer RM, Krane SM, Potts Jr JT & Bloch KJ 1972 An evaluation of antibodies and clinical resistance to salmon calcitonin. Journal of Clinical Investigation 51 2331–2338. (https://doi.org/10.1172/JCI107044)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Singer FR, Fredericks RS & Minkin C 1980 Salmon calcitonin therapy for Paget’s disease of bone. The problem of acquired clinical resistance. Arthritis and Rheumatism 23 1148–1154. (https://doi.org/10.1002/art.1780231012)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Stephens AS, Stephens SR & Morrison NA 2011 Internal control genes for quantitative RT-PCR expression analysis in mouse osteoblasts, osteoclasts and macrophages. BMC Research Notes 4 410. (https://doi.org/10.1186/1756-0500-4-410)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Stevenson JC, Hillyard CJ, MacIntyre I, Cooper H & Whitehead MI 1979 A physiological role for calcitonin: protection of the maternal skeleton. Lancet 2 769–770. (https://doi.org/10.1016/s0140-6736(7992117-2)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Tang SY, Herber RP, Ho SP & Alliston T 2012 Matrix metalloproteinase-13 is required for osteocytic perilacunar remodeling and maintains bone fracture resistance. Journal of Bone and Mineral Research 27 1936–1950. (https://doi.org/10.1002/jbmr.1646)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Tikellis C, Xuereb L, Casley D, Brasier G, Cooper ME & Wookey PJ 2003 Calcitonin receptor isoforms expressed in the developing rat kidney. Kidney International 63 416–426. (https://doi.org/10.1046/j.1523-1755.2003.00754.x)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Toverud SU, Cooper CW & Munson PL 1978 Calcium metabolism during lactation: elevated blood levels of calcitonin. Endocrinology 103 472–479. (https://doi.org/10.1210/endo-103-2-472)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Turner AG, Tjahyono F, Chiu WS, Skinner J, Sawyer R, Moore AJ, Morris HA, Findlay DM, Zajac JD & Davey RA 2011 The role of the calcitonin receptor in protecting against induced hypercalcemia is mediated via its actions in osteoclasts to inhibit bone resorption. Bone 48 354–361. (https://doi.org/10.1016/j.bone.2010.09.013)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Tverberg LA, Gustafson MF, Scott TL, Arzumanova IV, Provost ER, Yan AW & Rawie SA 2000 Induction of calcitonin and calcitonin receptor expression in rat mammary tissue during pregnancy. Endocrinology 141 3696–3702. (https://doi.org/10.1210/endo.141.10.7712)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • VanHouten JN & Wysolmerski JJ 2003 Low estrogen and high parathyroid hormone-related peptide levels contribute to accelerated bone resorption and bone loss in lactating mice. Endocrinology 144 5521–5529. (https://doi.org/10.1210/en.2003-0892)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Wallach S, Rousseau G, Martin L & Azria M 1999 Effects of calcitonin on animal and in vitro models of skeletal metabolism. Bone 25 509–516. (https://doi.org/10.1016/s8756-3282(9900200-8)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Weivoda MM, Youssef SJ & Oursler MJ 2017 Sclerostin expression and functions beyond the osteocyte. Bone 96 45–50. (https://doi.org/10.1016/j.bone.2016.11.024)

  • Woodrow JP, Sharpe CJ, Fudge NJ, Hoff AO, Gagel RF & Kovacs CS 2006 Calcitonin plays a critical role in regulating skeletal mineral metabolism during lactation. Endocrinology 147 4010–4021. (https://doi.org/10.1210/en.2005-1616)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Wu H, Xu G & Li YP 2009 Atp6v0d2 is an essential component of the osteoclast-specific proton pump that mediates extracellular acidification in bone resorption. Journal of Bone and Mineral Research 24 871–885. (https://doi.org/10.1359/jbmr.081239)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Wysolmerski JJ 2013 Osteocytes remove and replace perilacunar mineral during reproductive cycles. Bone 54 230–236. (https://doi.org/10.1016/j.bone.2013.01.025)

    • PubMed
    • Search Google Scholar
    • Export Citation