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Cellular and Molecular Life Sciences

, Volume 76, Issue 2, pp 355–367 | Cite as

Chemokine-like receptor 1 deficiency leads to lower bone mass in male mice

  • Huashan Zhao
  • Dewen Yan
  • Liang Xiang
  • Chen Huang
  • Jian Li
  • Xiangfang Yu
  • Binbin Huang
  • Baobei Wang
  • Jie Chen
  • Tianxia Xiao
  • Pei-Gen RenEmail author
  • Jian V. ZhangEmail author
Original Article
  • 219 Downloads

Abstract

The adipokine Chemerin and its receptor, chemokine-like receptor 1 (CMKLR1), are associated with osteoblastogenic differentiation of mesenchymal stem cells (MSCs) and osteoclastogenic differentiation of osteoclast precursors in vitro, suggesting that CMKLR1 would affect the bone mineral density (BMD). However, the role of CMKLR1 on BMD in vivo remains unknown. Here, using CMKLR1 knockout mouse model, we unveiled that CMKLR1 effected the amount of Leydig cells in testis and regulated androgen-dependent bone maintenance in male mice, which exhibited lower serum testosterone levels, thereby reducing the trabecular bone mass. Correspondingly, the mRNA expression of testosterone synthesis enzymes in testis decreased. The bone tissue also showed decreased mRNAs expression of osteogenic markers and increased mRNA levels for osteoclast markers. Furthermore, by in vitro differentiation models, we found CMKLR1-deficiency could break the balance between osteoblastogenesis and osteoclastogenesis that caused a shift from osteogenic to adipogenic differentiation in MSCs and enhanced osteoclast formation. In addition, bone mass increase in CMKLR1 KO male mice can be promoted by treatment with 5α-dihydrotestosterone (DHT), and the inactivation of CMKLR1 in male wild-type (WT) mice with antagonist treatment can lead to low bone mass. Taken together, these data indicate that CMKLR1 positively regulates bone metabolism through mediating testosterone production and the balance between osteoblast and osteoclast formation.

Keywords

Osteoporosis Chemerin CMKLR1 Adipokine Testosterone 

Notes

Acknowledgements

This study was supported by the National Natural Science Foundation of China (81771611 and 31671562), Guangdong Natural Science Foundation (2017A020211033), the Science and Technology Innovation Fund of Shenzhen (JCYJ20170413165233512, JCYJ20170412140326739, JCYJ20170413165503382, JCYJ20170815123502541, JCYJ20170814175916411, and JCYJ20170307165601938).

Author contributions

JZ, LX, HZ and PR conceived and designed the experiments; LX, HZ, BW, CH, XT, JL, XY and BH performed the experiments; LX, HZ, JZ DY, XY and BH analyzed the data; JC, DY and XT contributed reagents/materials/analysis tools/housing animals; HZ and LX wrote the manuscript. All authors reviewed and approved the final version of the manuscript.

Supplementary material

18_2018_2944_MOESM1_ESM.doc (3.1 mb)
Supplementary material 1 (DOC 3125 kb)

References

  1. 1.
    Rachner TD, Khosla S, Hofbauer LC (2011) Osteoporosis: now and the future. Lancet 377(9773):1276–1287.  https://doi.org/10.1016/S0140-6736(10)62349-5 CrossRefGoogle Scholar
  2. 2.
    Zaidi M (2007) Skeletal remodeling in health and disease. Nat Med 13(7):791–801.  https://doi.org/10.1038/nm1593 CrossRefGoogle Scholar
  3. 3.
    Sidlauskas KM, Sutton EE, Biddle MA (2014) Osteoporosis in men: epidemiology and treatment with denosumab. Clin Interv Aging 9:593–601.  https://doi.org/10.2147/CIA.S51940 Google Scholar
  4. 4.
    Korpi-Steiner N, Milhorn D, Hammett-Stabler C (2014) Osteoporosis in men. Clin Biochem 47(10–11):950–959.  https://doi.org/10.1016/j.clinbiochem.2014.03.026 CrossRefGoogle Scholar
  5. 5.
    Ebeling PR (2008) Clinical practice. Osteoporosis in men. New Engl J Med 358(14):1474–1482.  https://doi.org/10.1056/nejmcp0707217 CrossRefGoogle Scholar
  6. 6.
    Ferlin A, Selice R, Carraro U, Foresta C (2013) Testicular function and bone metabolism–beyond testosterone. Nat Rev Endocrinol 9(9):548–554.  https://doi.org/10.1038/nrendo.2013.135 CrossRefGoogle Scholar
  7. 7.
    Nakamura T, Imai Y, Matsumoto T, Sato S, Takeuchi K, Igarashi K, Harada Y, Azuma Y, Krust A, Yamamoto Y, Nishina H, Takeda S, Takayanagi H, Metzger D, Kanno J, Takaoka K, Martin TJ, Chambon P, Kato S (2007) Estrogen prevents bone loss via estrogen receptor alpha and induction of Fas ligand in osteoclasts. Cell 130(5):811–823.  https://doi.org/10.1016/j.cell.2007.07.025 CrossRefGoogle Scholar
  8. 8.
    Falahati-Nini A, Riggs BL, Atkinson EJ, O’Fallon WM, Eastell R, Khosla S (2000) Relative contributions of testosterone and estrogen in regulating bone resorption and formation in normal elderly men. J Clin Investig 106(12):1553–1560.  https://doi.org/10.1172/JCI10942 CrossRefGoogle Scholar
  9. 9.
    Kondoh S, Inoue K, Igarashi K, Sugizaki H, Shirode-Fukuda Y, Inoue E, Yu T, Takeuchi JK, Kanno J, Bonewald LF, Imai Y (2014) Estrogen receptor alpha in osteocytes regulates trabecular bone formation in female mice. Bone 60:68–77.  https://doi.org/10.1016/j.bone.2013.12.005 CrossRefGoogle Scholar
  10. 10.
    Windahl SH, Borjesson AE, Farman HH, Engdahl C, Moverare-Skrtic S, Sjogren K, Lagerquist MK, Kindblom JM, Koskela A, Tuukkanen J, Divieti Pajevic P, Feng JQ, Dahlman-Wright K, Antonson P, Gustafsson JA, Ohlsson C (2013) Estrogen receptor-alpha in osteocytes is important for trabecular bone formation in male mice. Proc Natl Acad Sci USA 110(6):2294–2299.  https://doi.org/10.1073/pnas.1220811110 CrossRefGoogle Scholar
  11. 11.
    Clarke BL, Khosla S (2009) Androgens and bone. Steroids 74(3):296–305.  https://doi.org/10.1016/j.steroids.2008.10.003 CrossRefGoogle Scholar
  12. 12.
    Kawano H, Sato T, Yamada T, Matsumoto T, Sekine K, Watanabe T, Nakamura T, Fukuda T, Yoshimura K, Yoshizawa T, Aihara K, Yamamoto Y, Nakamichi Y, Metzger D, Chambon P, Nakamura K, Kawaguchi H, Kato S (2003) Suppressive function of androgen receptor in bone resorption. Proc Natl Acad Sci USA 100(16):9416–9421.  https://doi.org/10.1073/pnas.1533500100 CrossRefGoogle Scholar
  13. 13.
    Bozaoglu K, Bolton K, McMillan J, Zimmet P, Jowett J, Collier G, Walder K, Segal D (2007) Chemerin is a novel adipokine associated with obesity and metabolic syndrome. Endocrinology 148(10):4687–4694.  https://doi.org/10.1210/en.2007-0175 CrossRefGoogle Scholar
  14. 14.
    Wittamer V, Franssen JD, Vulcano M, Mirjolet JF, Le Poul E, Migeotte I, Brezillon S, Tyldesley R, Blanpain C, Detheux M, Mantovani A, Sozzani S, Vassart G, Parmentier M, Communi D (2003) Specific recruitment of antigen-presenting cells by chemerin, a novel processed ligand from human inflammatory fluids. J Exp Med 198(7):977–985.  https://doi.org/10.1084/jem.20030382 CrossRefGoogle Scholar
  15. 15.
    Ernst MC, Sinal CJ (2010) Chemerin: at the crossroads of inflammation and obesity. Trends Endocrinol Metab TEM 21(11):660–667.  https://doi.org/10.1016/j.tem.2010.08.001 CrossRefGoogle Scholar
  16. 16.
    Luangsay S, Wittamer V, Bondue B, De Henau O, Rouger L, Brait M, Franssen JD, de Nadai P, Huaux F, Parmentier M (2009) Mouse ChemR23 is expressed in dendritic cell subsets and macrophages, and mediates an anti-inflammatory activity of chemerin in a lung disease model. J Immunol 183(10):6489–6499.  https://doi.org/10.4049/jimmunol.0901037 CrossRefGoogle Scholar
  17. 17.
    Barnea G, Strapps W, Herrada G, Berman Y, Ong J, Kloss B, Axel R, Lee KJ (2008) The genetic design of signaling cascades to record receptor activation. Proc Natl Acad Sci USA 105(1):64–69.  https://doi.org/10.1073/pnas.0710487105 CrossRefGoogle Scholar
  18. 18.
    Zabel BA, Nakae S, Zuniga L, Kim JY, Ohyama T, Alt C, Pan J, Suto H, Soler D, Allen SJ, Handel TM, Song CH, Galli SJ, Butcher EC (2008) Mast cell-expressed orphan receptor CCRL2 binds chemerin and is required for optimal induction of IgE-mediated passive cutaneous anaphylaxis. J Exp Med 205(10):2207–2220.  https://doi.org/10.1084/jem.20080300 CrossRefGoogle Scholar
  19. 19.
    Goralski KB, McCarthy TC, Hanniman EA, Zabel BA, Butcher EC, Parlee SD, Muruganandan S, Sinal CJ (2007) Chemerin, a novel adipokine that regulates adipogenesis and adipocyte metabolism. J Biol Chem 282(38):28175–28188.  https://doi.org/10.1074/jbc.M700793200 CrossRefGoogle Scholar
  20. 20.
    Ramos-Junior ES, Leite GA, Carmo-Silva CC, Taira TM, Neves KB, Colon DF, da Silva LA, Salvador SL, Tostes RC, Cunha FQ, Fukada SY (2017) Adipokine chemerin bridges metabolic dyslipidemia and alveolar bone loss in Mice. J Bone Miner Res Off J Am Soc Bone Miner Res 32(5):974–984.  https://doi.org/10.1002/jbmr.3072 CrossRefGoogle Scholar
  21. 21.
    Muruganandan S, Roman AA, Sinal CJ (2010) Role of chemerin/CMKLR1 signaling in adipogenesis and osteoblastogenesis of bone marrow stem cells. J Bone Miner Res Off J Am Soc Bone Miner Res 25(2):222–234.  https://doi.org/10.1359/jbmr.091106 CrossRefGoogle Scholar
  22. 22.
    Muruganandan S, Parlee SD, Rourke JL, Ernst MC, Goralski KB, Sinal CJ (2011) Chemerin, a novel peroxisome proliferator-activated receptor gamma (PPARgamma) target gene that promotes mesenchymal stem cell adipogenesis. J Biol Chem 286(27):23982–23995.  https://doi.org/10.1074/jbc.M111.220491 CrossRefGoogle Scholar
  23. 23.
    Muruganandan S, Dranse HJ, Rourke JL, McMullen NM, Sinal CJ (2013) Chemerin neutralization blocks hematopoietic stem cell osteoclastogenesis. Stem Cells 31(10):2172–2182.  https://doi.org/10.1002/stem.1450 CrossRefGoogle Scholar
  24. 24.
    Li J, Xiang L, Jiang X, Teng B, Sun Y, Chen G, Chen J, Zhang JV, Ren PG (2017) Investigation of bioeffects of G protein-coupled receptor 1 on bone turnover in male mice. J Orthop Transl 10:42–51.  https://doi.org/10.1016/j.jot.2017.05.001 Google Scholar
  25. 25.
    Dou Y, Zhang XJ, Xu XQ, Zhou X, Han SL, Wang RB, Su M, Li XH, Zhang JX (2015) Multiple noncovalent interactions mediated one-pot therapeutic assemblies for the effective treatment of atherosclerosis. J Mater Chem B 3(37):7355–7365.  https://doi.org/10.1039/c5tb01474c CrossRefGoogle Scholar
  26. 26.
    Chang YF, Lee-Chang JS, Panneerdoss S, MacLean JA, Rao MK (2011) Isolation of Sertoli, Leydig, and spermatogenic cells from the mouse testis. BioTechniques 51(5):341–342.  https://doi.org/10.2144/000113764 CrossRefGoogle Scholar
  27. 27.
    Chen Q, Shou P, Zhang L, Xu C, Zheng C, Han Y, Li W, Huang Y, Zhang X, Shao C, Roberts AI, Rabson AB, Ren G, Zhang Y, Wang Y, Denhardt DT, Shi Y (2014) An osteopontin-integrin interaction plays a critical role in directing adipogenesis and osteogenesis by mesenchymal stem cells. Stem cells 32(2):327–337.  https://doi.org/10.1002/stem.1567 CrossRefGoogle Scholar
  28. 28.
    Graham KL, Zhang JV, Lewen S, Burke TM, Dang T, Zoudilova M, Sobel RA, Butcher EC, Zabel BA (2014) A novel CMKLR1 small molecule antagonist suppresses CNS autoimmune inflammatory disease. PLoS One 9(12):e112925.  https://doi.org/10.1371/journal.pone.0112925 CrossRefGoogle Scholar
  29. 29.
    Thongchote K, Svasti S, Teerapornpuntakit J, Krishnamra N, Charoenphandhu N (2014) Running exercise alleviates trabecular bone loss and osteopenia in hemizygous beta-globin knockout thalassemic mice. Am J Physiol Endocrinol Metab 306(12):E1406–E1417.  https://doi.org/10.1152/ajpendo.00111.2014 CrossRefGoogle Scholar
  30. 30.
    Kim H, Lee K, Ko CY, Kim HS, Shin HI, Kim T, Lee SH, Jeong D (2012) The role of nacreous factors in preventing osteoporotic bone loss through both osteoblast activation and osteoclast inactivation. Biomaterials 33(30):7489–7496.  https://doi.org/10.1016/j.biomaterials.2012.06.098 CrossRefGoogle Scholar
  31. 31.
    Chen H, Jin S, Guo J, Kombairaju P, Biswal S, Zirkin BR (2015) Knockout of the transcription factor Nrf2: effects on testosterone production by aging mouse Leydig cells. Mol Cell Endocrinol 409:113–120.  https://doi.org/10.1016/j.mce.2015.03.013 CrossRefGoogle Scholar
  32. 32.
    Li L, Ma P, Huang C, Liu Y, Zhang Y, Gao C, Xiao T, Ren PG, Zabel BA, Zhang JV (2014) Expression of chemerin and its receptors in rat testes and its action on testosterone secretion. J Endocrinol 220(2):155–163.  https://doi.org/10.1530/JOE-13-0275 CrossRefGoogle Scholar
  33. 33.
    Mattern A, Zellmann T, Beck-Sickinger AG (2014) Processing, signaling, and physiological function of chemerin. IUBMB Life 66(1):19–26.  https://doi.org/10.1002/iub.1242 CrossRefGoogle Scholar
  34. 34.
    Wang F, Wang PX, Wu XL, Dang SY, Chen Y, Ni YY, Gao LH, Lu SY, Kuang Y, Huang L, Fei J, Wang ZG, Pang XF (2013) Deficiency of adiponectin protects against ovariectomy-induced osteoporosis in mice. PLoS One 8(7):e68497.  https://doi.org/10.1371/journal.pone.0068497 CrossRefGoogle Scholar
  35. 35.
    Ducy P, Amling M, Takeda S, Priemel M, Schilling AF, Beil FT, Shen J, Vinson C, Rueger JM, Karsenty G (2000) Leptin inhibits bone formation through a hypothalamic relay: a central control of bone mass. Cell 100(2):197–207CrossRefGoogle Scholar
  36. 36.
    Gao L, Faibish D, Fredman G, Herrera BS, Chiang N, Serhan CN, Van Dyke TE, Gyurko R (2013) Resolvin E1 and chemokine-like receptor 1 mediate bone preservation. J Immunol 190(2):689–694.  https://doi.org/10.4049/jimmunol.1103688 CrossRefGoogle Scholar
  37. 37.
    Zhu M, Van Dyke TE, Gyurko R (2013) Resolvin E1 regulates osteoclast fusion via DC-STAMP and NFATc1. FASEB J 27(8):3344–3353.  https://doi.org/10.1096/fj.12-220228 CrossRefGoogle Scholar
  38. 38.
    Rouger L, Denis GR, Luangsay S, Parmentier M (2013) ChemR23 knockout mice display mild obesity but no deficit in adipocyte differentiation. J Endocrinol 219(3):279–289.  https://doi.org/10.1530/JOE-13-0106 CrossRefGoogle Scholar
  39. 39.
    Gruben N, Aparicio Vergara M, Kloosterhuis NJ, van der Molen H, Stoelwinder S, Youssef S, de Bruin A, Delsing DJ, Kuivenhoven JA, van de Sluis B, Hofker MH, Koonen DP (2014) Chemokine-like receptor 1 deficiency does not affect the development of insulin resistance and nonalcoholic fatty liver disease in mice. PLoS One 9(4):e96345.  https://doi.org/10.1371/journal.pone.0096345 CrossRefGoogle Scholar
  40. 40.
    Ernst MC, Haidl ID, Zuniga LA, Dranse HJ, Rourke JL, Zabel BA, Butcher EC, Sinal CJ (2012) Disruption of the chemokine-like receptor-1 (CMKLR1) gene is associated with reduced adiposity and glucose intolerance. Endocrinology 153(2):672–682.  https://doi.org/10.1210/en.2011-1490 CrossRefGoogle Scholar
  41. 41.
    Wargent ET, Zaibi MS, O’Dowd JF, Cawthorne MA, Wang SJ, Arch JR, Stocker CJ (2015) Evidence from studies in rodents and in isolated adipocytes that agonists of the chemerin receptor CMKLR1 may be beneficial in the treatment of type 2 diabetes. PeerJ 3:e753.  https://doi.org/10.7717/peerj.753 CrossRefGoogle Scholar
  42. 42.
    Syed F, Khosla S (2005) Mechanisms of sex steroid effects on bone. Biochem Biophys Res Commun 328(3):688–696.  https://doi.org/10.1016/j.bbrc.2004.11.097 CrossRefGoogle Scholar
  43. 43.
    Huber DM, Bendixen AC, Pathrose P, Srivastava S, Dienger KM, Shevde NK, Pike JW (2001) Androgens suppress osteoclast formation induced by RANKL and macrophage-colony stimulating factor. Endocrinology 142(9):3800–3808.  https://doi.org/10.1210/endo.142.9.8402 CrossRefGoogle Scholar
  44. 44.
    Muruganandan S, Roman AA, Sinal CJ (2009) Adipocyte differentiation of bone marrow-derived mesenchymal stem cells: cross talk with the osteoblastogenic program. Cell Mol Life Sci CMLS 66(2):236–253.  https://doi.org/10.1007/s00018-008-8429-z CrossRefGoogle Scholar
  45. 45.
    Muruganandan S, Sinal CJ (2014) The impact of bone marrow adipocytes on osteoblast and osteoclast differentiation. IUBMB Life 66(3):147–155.  https://doi.org/10.1002/iub.1254 CrossRefGoogle Scholar
  46. 46.
    Muruganandan S, Govindarajan R, McMullen NM, Sinal CJ (2017) Chemokine-like receptor 1 is a novel Wnt target gene that regulates mesenchymal stem cell differentiation. Stem Cell 35(3):711–724.  https://doi.org/10.1002/stem.2520 CrossRefGoogle Scholar
  47. 47.
    Takahashi M, Okimura Y, Iguchi G, Nishizawa H, Yamamoto M, Suda K, Kitazawa R, Fujimoto W, Takahashi K, Zolotaryov FN, Hong KS, Kiyonari H, Abe T, Kaji H, Kitazawa S, Kasuga M, Chihara K, Takahashi Y (2011) Chemerin regulates beta-cell function in mice. Sci Rep 1:123.  https://doi.org/10.1038/srep00123 CrossRefGoogle Scholar
  48. 48.
    Huang C, Wang M, Ren L, Xiang L, Chen J, Li M, Xiao T, Ren P, Xiong L, Zhang JV (2016) CMKLR1 deficiency influences glucose tolerance and thermogenesis in mice on high fat diet. Biochem Biophys Res Commun 473(2):435–441.  https://doi.org/10.1016/j.bbrc.2016.03.026 CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  • Huashan Zhao
    • 1
  • Dewen Yan
    • 2
  • Liang Xiang
    • 1
  • Chen Huang
    • 1
  • Jian Li
    • 3
  • Xiangfang Yu
    • 3
  • Binbin Huang
    • 1
    • 4
  • Baobei Wang
    • 1
  • Jie Chen
    • 1
  • Tianxia Xiao
    • 1
  • Pei-Gen Ren
    • 2
    Email author
  • Jian V. Zhang
    • 1
    Email author
  1. 1.Laboratory for Reproductive Health, Shenzhen Institutes of Advanced TechnologyChinese Academy of SciencesShenzhenChina
  2. 2.Department of EndocrinologyThe First Affiliated Hospital of Shenzhen UniversityShenzhenChina
  3. 3.Center for Translational Medicine Research and Development, Shenzhen Institutes of Advanced TechnologyChinese Academy of SciencesShenzhenChina
  4. 4.Shenzhen College of Advanced TechnologyUniversity of Chinese Academy of SciencesShenzhenChina

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