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The skeleton as an endocrine organ

Nature Reviews Rheumatology volume 8, pages 674–683 (2012)Cite this article

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Abstract

Surprising new discoveries in the field of skeletal biology show that bone cells produce endocrine hormones that regulate phosphate and glucose homeostasis. In this Review, we examine the features of these new endocrine pathways and discuss their physiological importance in the context of our current understanding of energy metabolism and mineral homeostasis. Consideration of evolutionary and comparative biology provides clues that a key driving force for the emergence of these hormonal pathways was the development of a large, energy-expensive musculoskeletal system. Specialized bone cells also evolved and produced endocrine hormones to integrate the skeleton in global mineral and nutrient homeostasis. The recognition of bone as a true endocrine organ represents a fertile area for further research and should improve the diagnosis and treatment of metabolic diseases such as osteoporosis and diabetes mellitus.

Key Points

  • The endochondral skeleton evolved specialized bone cells (osteocytes), which produce endocrine hormones that integrate skeletal metabolism with global mineral and nutrient homeostasis

  • FGF23, made by osteocytes, regulates phosphate disposal from the body, providing an additional layer of control to aid parathyroid hormone in the maintenance of phosphate levels during bone resorption

  • Osteocalcin, produced by osteoblasts and osteocytes under the control of insulin, increases the efficiency of glucose utilization through its actions on the pancreas and adipocytes

  • Understanding the endocrine roles of the skeleton should improve the ability to diagnose and manage patients with a broad range of metabolic diseases, including osteoporosis and diabetes mellitus

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Figure 1: Microstructure and macrostructure of mammalian bone.
Figure 2: Integration of the skeleton in mineral and energy homeostasis.
Figure 3: The regulation of calcium and phosphate homeostasis by PTH, vitamin D and FGF23.
Figure 4: The osteocalcin axis in the regulation of energy metabolism by the skeleton.

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References

  1. Lu, Y. & Feng, J. Q. FGF23 in skeletal modeling and remodeling. Curr. Osteoporos Rep. 9, 103–108 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  2. Clemens, T. L. & Karsenty, G. The osteoblast: an insulin target cell controlling glucose homeostasis. J. Bone Miner. Res. 26, 677–680 (2011).

    Article  CAS  PubMed  Google Scholar 

  3. Carroll, R. Paleontology: between fish and amphibian. Nature 373, 389–390 (1995).

    Article  CAS  Google Scholar 

  4. Niedzwiedzki, G., Szrek, P., Narkiewicz, K., Narkiewicz, M. & Ahlberg, P. E. Tetrapod trackways from the early Middle Devonian period of Poland. Nature 463, 43–48 (2010).

    Article  CAS  PubMed  Google Scholar 

  5. Okabe, M. & Graham, A. The origin of the parathyroid gland. Proc. Natl Acad. Sci. USA 101, 17716–17719 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Botella, H., Blom, H., Dorka, M., Ahlberg, P. E. & Janvier, P. Jaws and teeth of the earliest bony fishes. Nature 448, 583–586 (2007).

    Article  CAS  PubMed  Google Scholar 

  7. Olsen, B. R., Reginato, A. M. & Wang, W. Bone development. Annu. Rev. Cell Dev. Biol. 16, 191–220 (2000).

    Article  CAS  PubMed  Google Scholar 

  8. Fernandez-Tresguerres-Hernandez-Gil, I., Alobera-Gracia, M. A., del- Canto-Pingarron, M. & Blanco-Jerez, L. Physiological bases of bone regeneration II. The remodeling process. Med. Oral Patol. Oral Cir. Bucal. 11, E151–E157 (2006).

    PubMed  Google Scholar 

  9. Chen, J. H., Liu, C., You, L. & Simmons, C. A. Boning up on Wolff's Law: mechanical regulation of the cells that make and maintain bone. J. Biomech. 43, 108–118 (2010).

    Article  PubMed  Google Scholar 

  10. Bonewald, L. F. The amazing osteocyte. J. Bone Miner. Res. 26, 229–238 (2011).

    CAS  PubMed  Google Scholar 

  11. Pead, M. J., Suswillo, R., Skerry, T. M., Vedi, S. & Lanyon, L. E. Increased 3H-uridine levels in osteocytes following a single short period of dynamic bone loading in vivo. Calcif. Tissue Int. 43, 92–96 (1988).

    Article  CAS  PubMed  Google Scholar 

  12. Marotti, G., Cane, V., Palazzini, S. & Palumbo, C. Structure–function relationships in the osteocyte. Ital. J. Min. Electro. Metab. 4, 93–106 (1990).

    Google Scholar 

  13. Cardoso, L. et al. Osteocyte apoptosis controls activation of intracortical resorption in response to bone fatigue. J. Bone Miner. Res. 24, 597–605 (2009).

    Article  CAS  PubMed  Google Scholar 

  14. Herman, B. C., Cardoso, L., Majeska, R. J., Jepsen, K. J. & Schaffler, M. B. Activation of bone remodeling after fatigue: differential response to linear microcracks and diffuse damage. Bone 47, 766–772 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Moester, M. J., Papapoulos, S. E., Lowik, C. W. & van Bezooijen, R. L. Sclerostin: current knowledge and future perspectives. Calcif. Tissue Int. 87, 99–107 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Nakashima, T. et al. Evidence for osteocyte regulation of bone homeostasis through RANKL expression. Nat. Med. 17, 1231–1234 (2011).

    Article  CAS  PubMed  Google Scholar 

  17. Xiong, J. et al. Matrix-embedded cells control osteoclast formation. Nat. Med. 17, 1235–1241 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Denver, R. J. et al. Comparative endocrinology in the 21st century. Integr. Comp. Biol. 49, 339–348 (2009).

    Article  PubMed  Google Scholar 

  19. Scharrer, E. & Scharrer, B. On glandular nerve cells and neurosecretory organs in invertebrates and vertebrates. Biol. Rev. Camb. Philos. Soc. 12, 185–216 (1937).

    Article  Google Scholar 

  20. Zera, A. J., Harshman, L. G. & Williams, T. D. Evolutionary endocrinology: The developing synthesis between endocrinology and evolutionary genetics. Ann. Rev. Ecol. Evol. System. 38, 793–817 (2007).

    Article  Google Scholar 

  21. Brown, E. M. in The Parathyroids: Basic and Clinical Concepts (eds Bilezikian, J. P., Marcus, R. & Levine, M. A.) 167–182 (Academic Press, San Diego, California, USA, 2001).

  22. Chan, S. J., Cao, Q. P. & Steiner, D. F. Evolution of the insulin superfamily: cloning of a hybrid insulin/insulin-like growth factor cDNA from amphioxus. Proc. Natl Acad. Sci. USA 87, 9319–9323 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Ebberink, R. H. M., Smit, A. B. & Vanminnen, J. The insulin family—evolution of structure and function in vertebrates and invertebrates. Biol. Bull. 177, 176–182 (1989).

    Article  CAS  Google Scholar 

  24. Nagamatsu, S., Chan, S. J., Falkmer, S. & Steiner, D. F. Evolution of the insulin gene superfamily. Sequence of a preproinsulin-like growth factor cDNA from the Atlantic hagfish. J. Biol. Chem. 266, 2397–2402 (1991).

    CAS  PubMed  Google Scholar 

  25. Bergwitz, C. & Juppner, H. Regulation of phosphate homeostasis by PTH, vitamin D, and FGF23. Annu. Rev. Med. 61, 91–104 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Legros, R., Balmain, N. & Bonel, G. Age-related changes in mineral of rat and bovine cortical bone. Calcif. Tissue Int. 41, 137–144 (1987).

    Article  CAS  PubMed  Google Scholar 

  27. Beck, L. et al. Targeted inactivation of Npt2 in mice leads to severe renal phosphate wasting, hypercalciuria, and skeletal abnormalities. Proc. Natl Acad. Sci. USA 95, 5372–5377 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Farrow, E. G. & White, K. E. Recent advances in renal phosphate handling. Nat. Rev. Nephrol. 6, 207–217 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  29. Burnett, C. H., Dent, C. E., Harper, C. & Warland, B. J. Vitamin D-resistant rickets. Analysis of twenty-four pedigrees with hereditary and sporadic cases. Am. J. Med. 36, 222–232 (1964).

    Article  CAS  PubMed  Google Scholar 

  30. Meyer, R. A. Jr, Meyer, M. H. & Gray, R. W. Parabiosis suggests a humoral factor is involved in X-linked hypophosphatemia in mice. J. Bone Miner. Res. 4, 493–500 (1989).

    Article  PubMed  Google Scholar 

  31. Morgan, J. M., Hawley, W. L., Chenoweth, A. I., Retan, W. J. & Diethelm, A. G. Renal transplantation in hypophosphatemia with vitamin D-resistant rickets. Arch. Intern. Med. 134, 549–552 (1974).

    Article  CAS  PubMed  Google Scholar 

  32. Nesbitt, T., Coffman, T. M., Griffiths, R. & Drezner, M. K. Crosstransplantation of kidneys in normal and Hyp mice. Evidence that the Hyp mouse phenotype is unrelated to an intrinsic renal defect. J. Clin. Invest. 89, 1453–1459 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Francis, F. et al. A gene (PEX) with homologies to endopeptidases is mutated in patients with X-linked hypophosphatemic rickets. The HYP Consortium. Nat. Genet. 11, 130–136 (1995).

    Article  CAS  Google Scholar 

  34. White, K. E. et al. Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23. Nat. Genet. 26, 345–348 (2000).

    Article  CAS  Google Scholar 

  35. White, K. E. et al. Autosomal-dominant hypophosphatemic rickets (ADHR) mutations stabilize FGF-23. Kidney Int. 60, 2079–2086 (2001).

    Article  CAS  PubMed  Google Scholar 

  36. Quarles, L. D. Endocrine functions of bone in mineral metabolism regulation. J. Clin. Invest. 118, 3820–3828 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Feng, J. Q. et al. Loss of DMP1 causes rickets and osteomalacia and identifies a role for osteocytes in mineral metabolism. Nat. Genet. 38, 1310–1315 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Lorenz-Depiereux, B. et al. DMP1 mutations in autosomal recessive hypophosphatemia implicate a bone matrix protein in the regulation of phosphate homeostasis. Nat. Genet. 38, 1248–1250 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Makitie, O. et al. Long-term clinical outcome and carrier phenotype in autosomal recessive hypophosphatemia caused by a novel DMP1 mutation. J. Bone Miner. Res. 25, 2165–2174 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Zhang, R. et al. Unique roles of phosphorus in endochondral bone formation and osteocyte maturation. J. Bone Miner. Res. 26, 1047–1056 (2011).

    Article  CAS  PubMed  Google Scholar 

  41. Farrow, E. G. & White, K. E. Tumor-induced osteomalacia. Expert Rev. Endocrinol. Metab. 4, 435–442 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Urakawa, I. et al. Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature 444, 770–774 (2006).

    Article  CAS  PubMed  Google Scholar 

  43. Kurosu, H. et al. Regulation of fibroblast growth factor-23 signaling by Klotho. J. Biol. Chem. 281, 6120–6123 (2006).

    Article  CAS  PubMed  Google Scholar 

  44. Shimada, T. et al. Targeted ablation of Fgf23 demonstrates an essential physiological role of FGF23 in phosphate and vitamin D metabolism. J. Clin. Invest. 113, 561–568 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Liu, S. et al. Fibroblast growth factor 23 is a counter-regulatory phosphaturic hormone for vitamin D. J. Am. Soc. Nephrol. 17, 1305–1315 (2006).

    Article  CAS  PubMed  Google Scholar 

  46. Ben-Dov, I. Z. et al. The parathyroid is a target organ for FGF23 in rats. J. Clin. Invest. 117, 4003–4008 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Krajisnik, T. et al. Fibroblast growth factor-23 regulates parathyroid hormone and 1α-hydroxylase expression in cultured bovine parathyroid cells. J. Endocrinol. 195, 125–131 (2007).

    Article  CAS  PubMed  Google Scholar 

  48. Emmett, M. A comparison of clinically useful phosphorus binders for patients with chronic kidney failure. Kidney Int. Suppl. 90, S25–S32 (2004).

    Article  CAS  Google Scholar 

  49. Mundy, G. R. & Guise, T. A. Hormonal control of calcium homeostasis. Clin. Chem. 45, 1347–1352 (1999).

    CAS  PubMed  Google Scholar 

  50. Liu, S. et al. Pathogenic role of Fgf23 in Hyp mice. Am. J. Physiol. Endocrinol. Metab. 291, E38–E49 (2006).

    Article  CAS  PubMed  Google Scholar 

  51. Ducy, P. et al. Leptin inhibits bone formation through a hypothalamic relay: a central control of bone mass. Cell 100, 197–207 (2000).

    Article  CAS  PubMed  Google Scholar 

  52. Takeda, S. et al. Leptin regulates bone formation via the sympathetic nervous system. Cell 111, 305–317 (2002).

    Article  CAS  PubMed  Google Scholar 

  53. Walther, D. J. et al. Synthesis of serotonin by a second tryptophan hydroxylase isoform. Science 299, 76–76 (2003).

    Article  CAS  PubMed  Google Scholar 

  54. Yadav, V. K. et al. A serotonin-dependent mechanism explains the leptin regulation of bone mass, appetite, and energy expenditure. Cell 138, 976–989 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Riggs, B. L., Khosla, S. & Melton, L. J. 3rd. Sex steroids and the construction and conservation of the adult skeleton. Endocr. Rev. 23, 279–302 (2002).

    Article  CAS  PubMed  Google Scholar 

  56. Gorski, J. P. Biomineralization of bone: a fresh view of the roles of non-collagenous proteins. Front. Biosci. 16, 2598–2621 (2011).

    Article  CAS  Google Scholar 

  57. Ducy, P. et al. Increased bone formation in osteocalcin-deficient mice. Nature 382, 448–452 (1996).

    Article  CAS  PubMed  Google Scholar 

  58. Lee, N. K. et al. Endocrine regulation of energy metabolism by the skeleton. Cell 130, 456–469 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Hauschka, P. V., Lian, J. B., Cole, D. E. & Gundberg, C. M. Osteocalcin and matrix Gla protein: vitamin K-dependent proteins in bone. Physiol. Rev. 69, 990–1047 (1989).

    Article  CAS  PubMed  Google Scholar 

  60. Merle, B. & Delmas, P. D. Normal carboxylation of circulating osteocalcin (bone Gla-protein) in Paget's disease of bone. Bone Miner. 11, 237–245 (1990).

    Article  CAS  PubMed  Google Scholar 

  61. Ferron, M. et al. Insulin signaling in osteoblasts integrates bone remodeling and energy metabolism. Cell 142, 296–308 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Fulzele, K. et al. Insulin receptor signaling in osteoblasts regulates postnatal bone acquisition and body composition. Cell 142, 309–319 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Rached, M. T. et al. FoxO1 expression in osteoblasts regulates glucose homeostasis through regulation of osteocalcin in mice. J. Clin. Invest. 120, 357–368 (2010).

    Article  CAS  PubMed  Google Scholar 

  64. Kousteni, S. FoxO1, the transcriptional chief of staff of energy metabolism. Bone 50, 437–443 (2012).

    Article  CAS  PubMed  Google Scholar 

  65. Delépine, M. et al. EIF2AK3, encoding translation initiation factor 2-α kinase 3, is mutated in patients with Wolcott–Rallison syndrome. Nat. Genet. 25, 406–409 (2000).

    Article  PubMed  Google Scholar 

  66. Harding, H. P. et al. Diabetes mellitus and exocrine pancreatic dysfunction in Perk−/− mice reveals a role for translational control in secretory cell survival. Mol. Cell 7, 1153–1163 (2001).

    Article  CAS  PubMed  Google Scholar 

  67. Ron, D. & Walter, P. Signal integration in the endoplasmic reticulum unfolded protein response. Nat. Rev. Mol. Cell Biol. 8, 519–529 (2007).

    Article  CAS  PubMed  Google Scholar 

  68. Scheuner, D. et al. Translational control is required for the unfolded protein response and in vivo glucose homeostasis. Mol. Cell 7, 1165–1176 (2001).

    Article  CAS  PubMed  Google Scholar 

  69. Oyadomari, S., Harding, H. P., Zhang, Y., Oyadomari, M. & Ron, D. Dephosphorylation of translation initiation factor 2alpha enhances glucose tolerance and attenuates hepatosteatosis in mice. Cell. Metab. 7, 520–532 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Yoshizawa, T. et al. The transcription factor ATF4 regulates glucose metabolism in mice through its expression in osteoblasts. J. Clin. Invest. 119, 2807–2817 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Kode, A. et al. FoxO1 protein cooperates with ATF4 protein in osteoblasts to control glucose homeostasis. J. Biol. Chem. 287, 8757–8768 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Salo, J., Lehenkari, P., Mulari, M., Metsikko, K. & Vaananen, H. K. Removal of osteoclast bone resorption products by transcytosis. Science 276, 270–273 (1997).

    Article  CAS  PubMed  Google Scholar 

  73. Hinoi, E. et al. The sympathetic tone mediates leptin's inhibition of insulin secretion by modulating osteocalcin bioactivity. J. Cell Biol. 183, 1235–1242 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Pasco, J. A. et al. β-adrenergic blockers reduce the risk of fracture partly by increasing bone mineral density: Geelong Osteoporosis Study. J. Bone Miner. Res. 19, 19–24 (2004).

    Article  CAS  PubMed  Google Scholar 

  75. Reid, I. R. et al. β-blocker use, BMD, and fractures in the study of osteoporotic fractures. J. Bone Miner. Res. 20, 613–618 (2005).

    Article  CAS  PubMed  Google Scholar 

  76. Schlienger, R. G., Kraenzlin, M. E., Jick, S. S. & Meier, C. R. Use of β-blockers and risk of fractures. JAMA 292, 1326–1332 (2004).

    Article  CAS  PubMed  Google Scholar 

  77. Turker, S., Karatosun, V. & Gunal, I. β-blockers increase bone mineral density. Clin. Orthop. Relat Res. 443, 73–74 (2006).

    Article  PubMed  Google Scholar 

  78. Egawa, K. et al. Protein-tyrosine phosphatase-1B negatively regulates insulin signaling in l6 myocytes and Fao hepatoma cells. J. Biol. Chem. 276, 10207–10211 (2001).

    Article  CAS  PubMed  Google Scholar 

  79. Kanazawa, I. et al. Serum osteocalcin level is associated with glucose metabolism and atherosclerosis parameters in type 2 diabetes mellitus. J. Clin. Endocrinol. Metab. 94, 45–49 (2009).

    Article  CAS  PubMed  Google Scholar 

  80. Kindblom, J. M. et al. Plasma osteocalcin is inversely related to fat mass and plasma glucose in elderly Swedish men. J. Bone Miner. Res. 24, 785–791 (2009).

    Article  CAS  PubMed  Google Scholar 

  81. Pittas, A. G., Harris, S. S., Eliades, M., Stark, P. & Dawson-Hughes, B. Association between serum osteocalcin and markers of metabolic phenotype. J. Clin. Endocrinol. Metab. 94, 827–832 (2009).

    Article  CAS  PubMed  Google Scholar 

  82. Saleem, U., Mosley, T. H. & Kullo, I. J. Serum osteocalcin is associated with measures of insulin resistance, adipokine levels, and the presence of metabolic syndrome. Arterioscler. Thromb. Vasc. Biol. 30, 1474–1478 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors wish to acknowledge grant support from the NIH: AR062074 (D. J. DiGirolamo); AR057868 (T. L. Clemens); and AR054447, AR055931 and AG032959 (S. Kousteni). T. L. Clemens is also the recipient of a Merit Review grant and Research Career Scientist Award from the Veterans Administration.

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  1. Department of Orthopaedic Surgery, Johns Hopkins University School of Medicine, 601 North Caroline Street, Baltimore, 21287, MD, USA

    Douglas J. DiGirolamo & Thomas L. Clemens

  2. Division of Endocrinology, Department of Medicine and Department of Physiology & Cellular Biophysics, Columbia University, The Russ Berrie Medical Sciences Pavilion, 1150 Saint Nicholas Avenue, New York, 10032, NY, USA

    Stavroula Kousteni

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DiGirolamo, D., Clemens, T. & Kousteni, S. The skeleton as an endocrine organ. Nat Rev Rheumatol 8, 674–683 (2012). https://doi.org/10.1038/nrrheum.2012.157

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