Skip to main content

Advertisement

Log in

Endocrine Crosstalk Between Muscle and Bone

  • Muscle and Bone (L Bonewald and M Harrick, Section Editors)
  • Published:
Current Osteoporosis Reports Aims and scope Submit manuscript

Abstract

The musculoskeletal system is a complex organ comprised of the skeletal bones, skeletal muscles, tendons, ligaments, cartilage, joints, and other connective tissue that physically and mechanically interact to provide animals and humans with the essential ability of locomotion. This mechanical interaction is undoubtedly essential for much of the diverse shape and forms observed in vertebrates and even in invertebrates with rudimentary musculoskeletal systems such as fish. It makes sense from a historical point of view that the mechanical theories of musculoskeletal development have had tremendous influence of our understanding of biology, because these relationships are clear and palpable. Less visible to the naked eye or even to the microscope is the biochemical interaction among the individual players of the musculoskeletal system. It was only in recent years that we have begun to appreciate that beyond this mechanical coupling of muscle and bones, these 2 tissues function at a higher level through crosstalk signaling mechanisms that are important for the function of the concomitant tissue. Our brief review attempts to present some of the key concepts of these new concepts and is outline to present muscles and bones as secretory/endocrine organs, the evidence for mutual genetic and tissue interactions, pathophysiological examples of crosstalk, and the exciting new directions for this promising field of research aimed at understanding the biochemical/molecular coupling of these 2 intimately associated tissues.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Pourquié O. Vertebrate Somitogenesis. Annu Rev Cell Dev Biol. 2001;17:311–50.

    Article  PubMed  Google Scholar 

  2. Rauch F, Schoenau E. The developing bone: slave or master of its cells and molecules? Pediatr Res. 2001;50:309–14.

    Article  CAS  PubMed  Google Scholar 

  3. Land C, Schoenau E. Fetal and postnatal bone development: reviewing the role of mechanical stimuli and nutrition. Best Pract Res Clin Endocrinol Metab. 2008;22:107–18.

    Article  PubMed  Google Scholar 

  4. Gunter KB, Almstedt HC, Janz KF. Physical activity in childhood may be the key to optimizing lifespan skeletal health. Exerc Sport Sci Rev. 2012;40:13–21. doi:10.1097/JES.1090b1013e318236e318235ee.

    Article  PubMed Central  PubMed  Google Scholar 

  5. Recker R, Lappe J, Davies K, Heaney R. Characterization of peri-menopausal bone loss: a prospective study. J Bone Miner Res. 2000;15:1965–73.

    Article  CAS  PubMed  Google Scholar 

  6. Hu MC, Shiizaki K, Kuro-o M, Moe OW. Fibroblast growth factor 23 and klotho: physiology and pathophysiology of an endocrine network of mineral metabolism. Annu Rev Physiol. 2013;75:503–33.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. Kurek JB et al. The role of leukemia inhibitory factor in skeletal muscle regeneration. Muscle Nerve. 1997;20:815–22.

    Article  CAS  PubMed  Google Scholar 

  8. Allen DL et al. Myostatin, activin receptor IIb, and follistatin-like-3 gene expression are altered in adipose tissue and skeletal muscle of obese mice. Am J Physiol Endocrinol Metab. 2008;294:E918–27.

    Article  CAS  PubMed  Google Scholar 

  9. Pedersen BK. Muscle as a secretory organ. Compr Physiol. 2013;3:1337–62. The discovery of Myostatin as the first muscle secreted factor was a landmark in the fields of muscle and musculoskeletal research. This discovery opened the door for the thinking that secreted factors from muscles could have organismal effects. Also, myostatin became known as the most important negative regulator of muscle mass.

    PubMed  Google Scholar 

  10. Allen DL, Hittel DS, McPherron AC. Expression and function of myostatin in obesity, diabetes, and exercise adaptation. Med Sci Sports Exerc. 2011;43:1828–35.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. Pedersen BK et al. Searching for the exercise factor: is IL-6 a candidate. J Muscle Res Cell Motil. 2003;24:113–9.

    Article  CAS  PubMed  Google Scholar 

  12. Reihmane D, Jurka A, Tretjakos P, Dela F. Increase in IL-6, TNF-a, and MMP-9, but not sICAM-1, concentrations depends on exercise duration. Eur J Appl Physiol. 2013;113:851–88.

    Article  CAS  PubMed  Google Scholar 

  13. Libardi CA, De Souza GV, Cavaglieri CR, Madruga VA, Chacon-Mikahil MP. Effect of resistance, endurance, and concurrent training on TNF-a, IL-6, and CRP. Med Sci Sports Exerc. 2012;44:50–5.

    Article  CAS  PubMed  Google Scholar 

  14. Matthews VB et al. Brain-derived neurotrophic factor is produced by skeletal muscle cells in response to contraction and enhances fat oxidation via activation of AMP-activated protein kinase. Diabetologia. 2009;52:1409–18.

    Article  CAS  PubMed  Google Scholar 

  15. Pedersen BK, Akerstrom TC, Nielsen AR, Fischer CP. Role of myokines in exercise and metabolism. J Appl Physiol. 2007;103(3):1093–8.

    Google Scholar 

  16. Pedersen L, Olsen CH, Pedersen BK, Hojman P. Muscle-derived expression of the chemokine CXCL1 attenuates diet-induced obesity and improves fatty acid oxidation in the muscle. Am J Physiol Endocrinol Metab. 2012;302:E831–40.

    Article  CAS  PubMed  Google Scholar 

  17. Seale P et al. PRDM16 controls a brown fat/skeletal muscle switch. Nature. 2008;454:961–7.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Quinn LS, Anderson BG, Strait-Bodey L, Stroud AM, Argiles JM. Oversecretion of interleukin-15 from skeletal muscle reduces adiposity. Am J Physiol Endocrinol Metab. 2009;296:E191–202. The demonstration that the overexpression of a muscle specific myokine could alter adiposity and also increase BMD is a remarkable indication that muscle can signal to bone in a biochemical manner.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Hee Park K et al. Circulating irisin in relation to insulin resistance and the metabolic syndrome. J Clin Endocrinol Metab. 2013;98:4899–907.

    Article  Google Scholar 

  20. Bortoluzzi S, Scannapieco P, Cestaro A, Danieli GA, Schiaffino S. Computational reconstruction of the human skeletal muscle secretome. Proteins. 2006;62:776–92.

    Article  CAS  PubMed  Google Scholar 

  21. Pedersen BK, Febbraio MA. Muscles, exercise and obesity: skeletal muscle as a secretory organ. Nat Rev Endocrinol. 2012;8:457–65.

    Article  CAS  PubMed  Google Scholar 

  22. Lee NK et al. Endocrine Regulation of Energy Metabolism by the Skeleton. Cell. 2007;130:456–69.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Lee NK, Karsenty G. Reciprocal regulation of bone and energy metabolism. Trends Endocrinol Metabol. 2008;19:161–6.

    Article  CAS  Google Scholar 

  24. DiGirolamo DJ, Clemens TL, Kousteni S. The skeleton as an endocrine organ. Nat Rev Rheumatol. 2012;8:674–83.

    Article  CAS  PubMed  Google Scholar 

  25. Guntar AR, Rosen CJ. Bone as an Endocrine Organ. Endocr Pract. 2012;18:758–62.

    Article  Google Scholar 

  26. Schaffler M, Kennedy O. Osteocyte signaling in bone. Curr Osteoporos Rep. 2012;10:118–25.

    Article  PubMed Central  PubMed  Google Scholar 

  27. Schwetz V, Pieber T, Obermayer-Pietsch B. Mechanisms in endocrinology: the endocrine role of the skeleton: background and clinical evidence. Eur J Endocrinol. 2012;166:959–67.

    Article  CAS  PubMed  Google Scholar 

  28. Karsenty G, Ferron M. The contribution of bone to whole-organism physiology. Nature. 2012;481:314–20.

    Article  CAS  PubMed  Google Scholar 

  29. Quarles LD. Skeletal secretion of FGF-23 regulates phosphate and vitamin D metabolism. Nat Rev Endocrinol. 2012;8:276–86.

    Article  CAS  PubMed  Google Scholar 

  30. Neve A, Corrado A, Cantatore FP. Osteocytes: central conductors of bone biology in normal and pathological conditions. Acta Physiol. 2012;204:317–30.

    Article  CAS  Google Scholar 

  31. Econs MJ et al. A PHEX Gene mutation is responsible for adult-onset Vitamin D-resistant hypophosphatemic osteomalacia: evidence that the disorder is not a distinct entity from X-Linked Hypophosphatemic Rickets. J Clin Endocrinol Metab. 1998;83:3459–62.

    CAS  PubMed  Google Scholar 

  32. Dallas SL, Prideaux M, Bonewald LF. The osteocyte: an endocrine cell. … and more. Endocr Rev. 2013;34:658–90.

    Article  CAS  PubMed  Google Scholar 

  33. The ADHR Consortium. Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23. Nat Genet. 2000;26:345–8.

    Article  Google Scholar 

  34. Quarles LD. FGF23, PHEX, and MEPE regulation of phosphate homeostasis and skeletal mineralization. Am J Physiol Endocrinol Metab. 2003;285:E1–9.

    CAS  PubMed  Google Scholar 

  35. Liu S et al. Pathogenic role of Fgf23 in Hyp mice. Am J Physiol Endocrinol Metab. 2006;291:E38–49.

    Article  CAS  PubMed  Google Scholar 

  36. Francis F et al. A gene (PEX) with homologies to endopeptidases is mutated in patients with X-linked hypophosphatemic rickets. Nat Genet. 1995;11:130–6.

    Article  CAS  Google Scholar 

  37. Rowe PSN et al. Distribution of Mutations in the PEX Gene in Families with X-linked Hypophosphataemic Rickets (HYP). Hum Molec Genet. 1997;6:539–49.

    Article  CAS  PubMed  Google Scholar 

  38. Dixon PH et al. Mutational analysis of PHEX gene in X-Linked Hypophosphatemia. J Clin Endocrinol Metab. 1998;83:3615–23.

    CAS  PubMed  Google Scholar 

  39. Faul C et al. FGF23 induces left ventricular hypertrophy. J Clin Invest. 2011;121:4393–408.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  40. Touchberry CD et al. FGF23 is a novel regulator of intracellular calcium and cardiac contractility in addition to cardiac hypertrophy. Am J Physiol Endocrinol Metab. 2013;304:E863–73.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  41. Winkler DG et al. Osteocyte control of bone formation via sclerostin, a novel BMP antagonist. EMBO J. 2003;22:6267–76.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  42. Frost HM. Bone's Mechanostat: a 2003 update. Anat Rec. 2003;275A:1081–101.

    Article  Google Scholar 

  43. Arden NK, Spector TD. Genetic influences on muscle strength, lean body mass, and bone mineral density: a twin study. J Bone Miner Res. 1997;12:2076–81.

    Article  CAS  PubMed  Google Scholar 

  44. Silventoinen K, Magnusson PKE, Tynelius P, Kaprio J, Rasmussen F. Heritability of body size and muscle strength in young adulthood: a study of one million Swedish men. Genet Epidemiol. 2008;32:341–9.

    Article  PubMed  Google Scholar 

  45. Prior SJ et al. Genetic and environmental influences on skeletal muscle phenotypes as a function of age and sex in large, multigenerational families of African heritage. J Appl Physiol. 2007;103:1121–7.

    Google Scholar 

  46. Costa A et al. Genetic inheritance effects on endurance and muscle strength. Sports Med. 2012;42:449–58.

    Article  PubMed  Google Scholar 

  47. Rivadeneira F et al. Twenty bone-mineral-density loci identified by large-scale meta-analysis of genome-wide association studies. Nat Genet. 2009;41:1199–206.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  48. Karasik D et al. Genome-wide pleiotropy of osteoporosis–related phenotypes: The Framingham study. J Bone Miner Res. 2010;25:1555–63.

    Article  PubMed Central  PubMed  Google Scholar 

  49. Duncan EL et al. Genome-wide association study using extreme truncate selection identifies novel genes affecting bone mineral density and fracture risk. PLoS Genet. 2011;7:e1001372.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  50. Estrada K et al. Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture. Nat Genet. 2012;44:491–501.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  51. Lee Y, Choi S, Ji J, Song G. Pathway analysis of genome-wide association study for bone mineral density. Mol Biol Rep. 2012;39:8099–106.

    Article  CAS  PubMed  Google Scholar 

  52. Ran S et al. Bivariate genome-wide association analyses identified genes with pleiotropic effects for femoral neck bone geometry and age at menarche. PLoS One. 2013;8:e60362.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  53. Savage SA et al. Genome-wide association study identifies two susceptibility loci for osteosarcoma. Nat Genet. 2013;45:799–803.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  54. Zhang L, et al. Multistage genome-wide association meta-analyses identified two new loci for bone mineral density. Hum Mol Genet. 2014;23(7):1923–33. doi:10.1093/hmg/ddt575.

    Google Scholar 

  55. Oei L, et al. A genome-wide copy number association study of osteoporotic fractures points to the 6p25.1 locus. J Med Genet. 2014;51(2):122–31. doi: 10.1136/jmedgenet-2013-102064.

    Google Scholar 

  56. Pérusse L et al. The Human gene map for performance and health-related fitness phenotypes: the 2002 Update. Med Sci Sports Exerc. 2003;35:1248–64.

    Article  PubMed  Google Scholar 

  57. Liu X-G et al. Genome-wide association and replication studies identified TRHR as an important gene for lean body mass. Am J Hum Genet. 2009;84:418–23.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  58. Thomis MA et al. Genome-wide linkage scan for resistance to muscle fatigue. Scand J Med Sci Sports. 2011;21:580–8.

    Article  CAS  PubMed  Google Scholar 

  59. Windelinckx A et al. Comprehensive fine mapping of chr12q12-14 and follow-up replication identify activin receptor 1B (ACVR1B) as a muscle strength gene. Eur J Hum Genet. 2011;19:208–15.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  60. Hai R et al. Genome-wide association study of copy number variation identified gremlin1 as a candidate gene for lean body mass. J Hum Genet. 2012;57:33–7.

    Article  CAS  PubMed  Google Scholar 

  61. Kuo T et al. Genome-wide analysis of glucocorticoid receptor-binding sites in myotubes identifies gene networks modulating insulin signaling. Proc Natl Acad Sci. 2012;109:11160–5.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  62. Guo Y-F et al. Suggestion of GLYAT gene underlying variation of bone size and body lean mass as revealed by a bivariate genome-wide association study. Hum Genet. 2013;132:189–99.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  63. Cheng Y et al. Body composition and gene expression QTL mapping in mice reveals imprinting and interaction effects. BMC Genet. 2013;14:103.

    Article  PubMed  Google Scholar 

  64. Keildson S, et al. Skeletal muscle expression of phosphofructokinase is influenced by genetic variation and associated with insulin sensitivity. Diabetes. 2014;63(3):1154-65. doi:10.2337/db13-1301.

    Google Scholar 

  65. Karasik D et al. Bivariate genome-wide linkage analysis of femoral bone traits and leg lean mass: The Framingham Study. J Bone Miner Res. 2009;24:710–8.

    Article  PubMed Central  PubMed  Google Scholar 

  66. Karasik D, Kiel DP. Evidence for pleiotropic factors in genetics of the musculoskeletal system. Bone. 2010;46:1226–37.

    Article  CAS  PubMed  Google Scholar 

  67. Gupta M et al. Identification of homogeneous genetic architecture of multiple genetically correlated traits by block clustering of genome-wide associations. J Bone Miner Res. 2011;26:1261–71.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  68. Sun L et al. Bivariate genome-wide association analyses of femoral neck bone geometry and appendicular lean mass. PLoS One. 2011;6:e27325.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  69. Karasik D, Cohen-Zinder M. Osteoporosis genetics: year 2011 in review. Bone Key Rep. 2012;1(114):1–5.

    Google Scholar 

  70. Edmondson DG, Lyons GE, Martin JF, Olson EN. Mef2 gene expression marks the cardiac and skeletal muscle lineages during mouse embryogenesis. Development. 1994;120:1251–63.

    CAS  PubMed  Google Scholar 

  71. Kramer I, Baertschi S, Halleux C, Keller H, Kneissel M. Mef2c deletion in osteocytes results in increased bone mass. J Bone Miner Res. 2012;27:360–73.

    Article  CAS  PubMed  Google Scholar 

  72. Grobet L et al. A deletion in the bovine myostatin gene causes the double-muscled phenotype in cattle. Nat Genet. 1997;17:71–4.

    Article  CAS  PubMed  Google Scholar 

  73. Kambadur R, Sharma M, Smith TPL, Bass JJ. Mutations in myostatin (GDF8) in Double-Muscled Belgian Blue and Piedmontese Cattle. Genome Res. 1997;7:910–5.

    CAS  PubMed  Google Scholar 

  74. McPherron AC, Lee S-J. Double muscling in cattle due to mutations in the myostatin gene. Proc Natl Acad Sci. 1997;94:12457–61.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  75. Clop A et al. A mutation creating a potential illegitimate microRNA target site in the myostatin gene affects muscularity in sheep. Nat Genet. 2006;38:813–8.

    Article  CAS  PubMed  Google Scholar 

  76. Mosher DS et al. A mutation in the myostatin gene increases muscle mass and enhances racing performance in Heterozygote Dogs. PLoS Genet. 2007;3:e79.

    Article  PubMed Central  PubMed  Google Scholar 

  77. Zhang GX, Zhao XH, Wang JY, Ding FX, Zhang L. Effect of an exon 1 mutation in the myostatin gene on the growth traits of the Bian chicken. Anim Genet. 2012;43:458–9.

    Article  PubMed  Google Scholar 

  78. Williams M. Myostatin mutation associated with gross muscle hypertrophy in a child. N Engl J Med. 2004;351:1030–1.

    Article  CAS  PubMed  Google Scholar 

  79. Pedersen BK, Febbraio MA. Muscles, exercise and obesity: skeletal muscle as a secretory organ. Nat Rev Endocrinol. 2012;8:457–65.

    Article  CAS  PubMed  Google Scholar 

  80. Elkasrawy M, Hamrick M. Myostatin (GDF-8) as a key factor linking muscle mass and bone structure. J Musculoskelet Neuronal Interact. 2010;10:56–63.

    CAS  PubMed Central  PubMed  Google Scholar 

  81. Williams NG et al. Endocrine actions of myostatin: systemic regulation of the IGF and IGF binding protein axis. Endocrinology. 2011;152:172–80.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  82. Perrini S et al. The GH/IGF1 axis and signaling pathways in the muscle and bone: mechanisms underlying age-related skeletal muscle wasting and osteoporosis. J Endocrinol. 2010;205:201–10.

    Article  CAS  PubMed  Google Scholar 

  83. Zacks SI, Sheff MF. Periosteal and metaplastic bone formation in mouse minced muscle regeneration. Lab Invest. 1982;46:405–12.

    CAS  PubMed  Google Scholar 

  84. Landry PS, Marino AA, Sadasivan KK, Albright JA. Effect of soft-tissue trauma on the early periosteal response of bone to injury. J Trauma. 2000;48:479–83.

    Article  CAS  PubMed  Google Scholar 

  85. Utvag SE, Iversen KB, Grundnes O, Reikeras O. Poor muscle coverage delays fracture healing in rats. Acta Orthop Scand. 2002;73:471–4.

    Article  PubMed  Google Scholar 

  86. Stein H et al. The muscle bed–a crucial factor for fracture healing: a physiological concept. Orthopedics. 2002;25:1379–83.

    PubMed  Google Scholar 

  87. Harry LE et al. Comparison of the healing of open tibial fractures covered with either muscle or fasciocutaneous tissue in a murine model. J Orthop Res. 2008;26:1238–44.

    Article  PubMed  Google Scholar 

  88. Gopal S, Majumder AG, Knight SL, De Boer P, Smith RM. Fix and Flap: the radical orthopedic and plastic treatment of severe open fractures of the tibia. J Bone Joint Surg (Br). 2000;82:959–66.

    Article  CAS  Google Scholar 

  89. Elkasrawy M et al. Immunolocalization of myostatin (GDF-8) following musculoskeletal injury and the effects of exogenous myostatin on muscle and bone healing. J Histochem Cytochem. 2012;60:22–30. This paper demonstrated that by inhibiting myostatin action early in the process of musculoskeletal injury, healing of both muscle and bone could be improved and accelerated.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  90. Schindeler A, Liu R, Little DG. The contribution of different cell lineages to bone repair: exploring a role for muscle stem cells. Differentiation. 2009;77:12–8.

    Article  CAS  PubMed  Google Scholar 

  91. Liu R, Schindeler A, Little DG. The potential role of muscle in bone repair. J Musculoskel Neuronal Interact. 2010;10:71–6.

    CAS  Google Scholar 

  92. Griffin XL, Costa ML, Parsons N, Smith N. Electromagnetic field stimulation for treating delayed union or non-union of long bone fractures in adults. Cochrane Database Syst Rev, 2011;CD008471.

  93. Leon-Salas WD et al. A dual mode pulsed electro-magnetic cell stimulator produces acceleration of myogenic differentiation. Recent Pat Biotechnol. 2013;7:71–81.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  94. Fakhouri TH, Ogden CL, Carroll MD, Kit BK, Flegal KM. Prevalence of obesity among older adults in the United States, 2007-2010. NCHS Data Brief. 2012;(106):1–8.

  95. Conboy IM et al. Rejuvenation of aged progenitor cells by exposure to a young systemic environment. Nature. 2005;433:760–4.

    Article  CAS  PubMed  Google Scholar 

  96. Jahn K et al. Skeletal muscle secreted factors prevent glucocorticoid-induced osteocyte apoptosis through activation of beta-catenin. Eur Cell Mater. 2012;24:197–209. discussion 209–110.

    CAS  PubMed Central  PubMed  Google Scholar 

Download references

Compliance with Ethics Guidelines

Conflict of Interest

M. Brotto and M. L. Johnson declare that they have no conflicts of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Marco Brotto.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Brotto, M., Johnson, M.L. Endocrine Crosstalk Between Muscle and Bone. Curr Osteoporos Rep 12, 135–141 (2014). https://doi.org/10.1007/s11914-014-0209-0

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11914-014-0209-0

Keywords

Navigation