close
Skip to main content
Springer Nature Link
Log in

The Multifaceted Effects of Osteocytic TGFβ Signaling on the Skeletal and Extraskeletal Functions of Bone

  • Published:
Save article
View saved research
Current Osteoporosis Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

To summarize the fundamental role of transforming growth factor beta (TGFβ) signaling in osteocytes and highlight the physiological and pathophysiological conditions stemming from the deregulation of this pathway in osteocytes.

Recent Findings

Osteocytes perform a myriad of skeletal and extraskeletal functions, including mechanosensing, coordinating bone remodeling, local bone matrix turnover, and maintaining systemic mineral homeostasis and global energy balance. Transforming growth factor-beta (TGFβ) signaling, which is crucial for embryonic and postnatal bone development and maintenance, has been found to be essential for several osteocyte functions. There is some evidence that TGFβ might be accomplishing these functions through crosstalk with the Wnt, PTH, and YAP/TAZ pathways in osteocytes, and a better understanding of this complex molecular network can help identify the pivotal convergence points responsible for distinct osteocyte functions.

Summary

This review provides recent updates on the interwoven signaling cascades coordinated by TGFβ signaling within osteocytes to support their skeletal and extraskeletal functions and highlights physiological and pathophysiological conditions implicating the role of TGFβ signaling in osteocytes.

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

Access this article

Log in via an institution

Subscribe and save

Springer+
from $39.99 /Month
  • Starting from 10 chapters or articles per month
  • Access and download chapters and articles from more than 300k books and 2,500 journals
  • Cancel anytime
View plans

Buy Now

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

Explore related subjects

Discover the latest articles, books and news in related subjects, suggested using machine learning.

References

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

  1. Sommerfeldt D, Rubin C. Biology of bone and how it orchestrates the form and function of the skeleton. Eur Spine J. 2001;10:S86–95.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Su N, Yang J, Xie Y, Du X, Chen H, Hong Z, Chen L. Bone function, dysfunction and its role in diseases including critical illness. Int J Biol Sci. 2019;15:776–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Fulzele K, Krause DS, Panaroni C, Saini V, Barry KJ, Liu X, Lotinun S, Baron R, Bonewald L, Feng JQ, Chen M, Weinstein LS, Wu JY, Kronenberg HM, Scadden DT, Divieti PP. Myelopoiesis is regulated by osteocytes through Gsα-dependent signaling. Blood. 2013;121:930–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Oury F, Sumara G, Sumara O, Ferron M, Chang H, Smith CE, Hermo L, Suarez S, Roth BL, Ducy P, Karsenty G. Endocrine regulation of male fertility by the skeleton. Cell. 2011;144:796–809.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Florencio-Silva R, Sasso GRS, Sasso-Cerri E, Simões MJ, Cerri PS. Biology of bone tissue: structure, function, and factors that influence bone cells. Biomed Res Int 2015:1–17.

  6. Compston J. Bone quality: what is it and how is it measured? Arq Bras Endocrinol Metabol. 2006;50:579–85.

    Article  PubMed  Google Scholar 

  7. Kennedy OD, Schaffler MB. The roles of osteocyte signaling in bone. J Am Acad Orthop Surg. 2012;20:670–1.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Sugawara Y, Kamioka H, Honjo T, Tezuka K, Takano-Yamamoto T. Three-dimensional reconstruction of chick calvarial osteocytes and their cell processes using confocal microscopy. Bone. 2005;36:877–83.

    Article  CAS  PubMed  Google Scholar 

  9. Bonewald LF. The amazing osteocyte. J Bone Miner Res. 2011;26:229–38.

    Article  CAS  PubMed  Google Scholar 

  10. Buenzli PR, Sims NA. Quantifying the osteocyte network in the human skeleton. Bone. 2015;75:144–50.

    Article  CAS  PubMed  Google Scholar 

  11. Weinbaum S, Cowin SC, Zeng Y. A model for the excitation of osteocytes by mechanical loading-induced bone fluid shear stresses. J Biomech. 1994;27:339–60.

    Article  CAS  PubMed  Google Scholar 

  12. Qin L, Liu W, Cao H, Xiao G. Molecular mechanosensors in osteocytes. Bone Res. 2020;8:23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Qing H, Ardeshirpour L, Divieti Pajevic P, Dusevich V, Jähn K, Kato S, Wysolmerski J, Bonewald LF. Demonstration of osteocytic perilacunar/canalicular remodeling in mice during lactation. J Bone Miner Res. 2012;27:1018–29.

    Article  CAS  PubMed  Google Scholar 

  14. Bonewald LF, Mundy GR. Role of transforming growth factor-beta in bone remodeling. Clin Orthop Relat Res 1990:261–76.

  15. Filvaroff E, Erlebacher A, Ye J-Q, Gitelman SE, Lotz J, Heillman M, Derynck R. Inhibition of TGF-β receptor signaling in osteoblasts leads to decreased bone remodeling and increased trabecular bone mass. Development. 1999;126:4267–79.

    Article  CAS  PubMed  Google Scholar 

  16. Janssens K, ten Dijke P, Janssens S, Van Hul W. Transforming growth factor-β1 to the bone. Endocr Rev. 2005;26:743–74.

    Article  CAS  PubMed  Google Scholar 

  17. Crane JL, Xian L, Cao X. Role of TGF-β signaling in coupling bone remodeling. In: Feng XH, Xu P, Lin X, editors. TGF-β Signaling. Methods in Molecular Biology. Humana Press 2016:1344:287–300.

  18. MacFarlane EG, Haupt J, Dietz HC, Shore EM. TGF-β family signaling in connective tissue and skeletal diseases. Cold Spring Harb Perspect Biol. 2017;9:a022269.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Tang SY, Alliston T. Regulation of postnatal bone homeostasis by TGFβ. Bonekey Rep. 2013;2:255.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Erlebacher A, Filvaroff EH, Ye J-Q, Derynck R. Osteoblastic responses to TGF-β during bone remodeling. Mol Biol Cell. 1998;9:1903–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Chang H, Brown CW, Matzuk MM. Genetic analysis of the mammalian transforming growth factor-β Superfamily. Endocr Rev. 2002;23:787–823.

    Article  CAS  PubMed  Google Scholar 

  22. Hinck AP, Mueller TD, Springer TA. Structural biology and evolution of the TGF-β family. Cold Spring Harb Perspect Biol. 2016;8:a022103.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Wang R, Zhu J, Dong X, Shi M, Lu C, Springer TA. GARP regulates the bioavailability and activation of TGFβ. Mol Biol Cell. 2012;23:1129–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Hinz B. The extracellular matrix and transforming growth factor-β1: tale of a strained relationship. Matrix Biol. 2015;47:54–65.

    Article  CAS  PubMed  Google Scholar 

  25. Poniatowski ŁA, Wojdasiewicz P, Gasik R, Szukiewicz D. Transforming growth factor beta family: insight into the role of growth factors in regulation of fracture healing biology and potential clinical applications. Mediators Inflamm. 2015;2015:1–17.

    Article  Google Scholar 

  26. Weivoda MM, Ruan M, Pederson L, Hachfeld C, Davey RA, Zajac JD, Westendorf JJ, Khosla S, Oursler MJ. Osteoclast TGF-β receptor signaling induces wnt1 secretion and couples bone resorption to bone formation. J Bone Miner Res. 2016;31:76–85.

    Article  CAS  PubMed  Google Scholar 

  27. Hata A, Chen Y-G. TGF-β Signaling from receptors to smads. Cold Spring Harb Perspect Biol. 2016;8:a022061.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Miyazawa K, Miyazono K. Regulation of TGF-β Family Signaling by Inhibitory Smads. Cold Spring Harb Perspect Biol. 2017;9:a022095.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Derynck R, Zhang YE. Smad-dependent and smad-independent pathways in TGF-β family signalling. Nature. 2003;425:577–84.

    Article  CAS  PubMed  Google Scholar 

  30. Wu M, Chen G, Li Y-P. TGF-β and BMP signaling in osteoblast, skeletal development, and bone formation, homeostasis and disease. Bone Res. 2016;4:16009.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Dallas SL, Alliston T, Bonewald LF. Chapter 53: transforming growth factor-ß. In: Bilezikian J, Martin TJ, Clemens T, Rosen C, editors. Principles of Bone Biology, 4th ed. 2007:1145–1166.

  32. Alliston T, Piek E, Derynck R. TGF-β family signaling in skeletal development, maintenance, and disease. In: Cold Spring Harbor Monograph Series. 2008:667–723.

  33. Rys JP, Monteiro DA, Alliston T. Mechanobiology of TGFβ signaling in the skeleton. Matrix Biol. 2016;52–54:413–25.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Sanford LP, Ormsby I, Groot ACG, Sariola H, Friedman R, Boivin GP, Cardell EL, Doetschman T. TGFβ2 knockout mice have multiple developmental defects that are non-overlapping with other TGFβ knockout phenotypes. Development. 1997;124:2659–70.

    Article  CAS  PubMed  Google Scholar 

  35. Proetzel G, Pawlowski SA, Wiles MV, Yin M, Boivin GP, Howles PN, Ding J, Ferguson MWJ, Doetschman T. Transforming growth factor–β3 is required for secondary palate fusion. Nat Genet. 1995;11:409–14.

    Article  CAS  PubMed  Google Scholar 

  36. Kaartinen V, Voncken JW, Shuler C, Warburton D, Bu D, Heisterkamp N, Groffen J. Abnormal lung development and cleft palate in mice lacking TGF–β3 indicates defects of epithelial–mesenchymal interaction. Nat Genet. 1995;11:415–21.

    Article  CAS  PubMed  Google Scholar 

  37. Seo H-S, Serra R. Deletion of Tgfbr2 in Prx1-cre expressing mesenchyme results in defects in development of the long bones and joints. Dev Biol. 2007;310:304–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Abou-Ezzi G, Supakorndej T, Zhang J, Anthony B, Krambs J, Celik H, Karpova D, Craft CS, Link DC. TGF-β Signaling plays an essential role in the lineage specification of mesenchymal stem/progenitor cells in fetal bone marrow. Stem Cell Reports. 2019;13:48–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Oka S, Oka K, Xu X, Sasaki T, Bringas P, Chai Y. Cell autonomous requirement for TGF-β signaling during odontoblast differentiation and dentin matrix formation. Mech Dev. 2007;124:409–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. • Qiu T, Wu X, Zhang F, Clemens TL, Wan M, Cao X. TGF-β type II receptor phosphorylates PTH receptor to integrate bone remodelling signalling. Nat Cell Biol. 2010;12:224–34. (This paper demonstrates that PTH induces an interaction between TβRII and PTH1R to regulate bone remodeling.)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Mohammad KS, Chen CG, Balooch G, Stebbins E, McKenna CR, Davis H, Niewolna M, Peng XH, Nguyen DH, Ionova-Martin SS, Bracey JW, Hogue WR, Wong DH, Ritchie RO, Suva LJ, Derynck R, Guise TA, Alliston T. Pharmacologic inhibition of the TGF-β type I receptor kinase has anabolic and anti-catabolic effects on bone. PLoS ONE. 2009;4:e5275.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Grafe I, Yang T, Alexander S, Homan EP, Lietman C, Jiang MM, Bertin T, Munivez E, Chen Y, Dawson B, Ishikawa Y, Weis MA, Sampath TK, Ambrose C, Eyre D, Bächinger HP, Lee B. Excessive transforming growth factor-β signaling is a common mechanism in osteogenesis imperfecta. Nat Med. 2014;20:670–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Itonaga I, Sabokbar A, Sun SG, Kudo O, Danks L, Ferguson D, Fujikawa Y, Athanasou NA. Transforming growth factor-β induces osteoclast formation in the absence of RANKL. Bone. 2004;34:57–64.

    Article  CAS  PubMed  Google Scholar 

  44. Karst M, Gorny G, Galvin RJS, Oursler MJ. Roles of stromal cell RANKL, OPG, and M-CSF expression in biphasic TGF-β regulation of osteoclast differentiation. J Cell Physiol. 2004;200:99–106.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Lee B, Oh Y, Jo S, Kim T-H, Ji JD. A dual role of TGF-β in human osteoclast differentiation mediated by Smad1 versus Smad3 signaling. Immunol Lett. 2019;206:33–40.

    Article  CAS  PubMed  Google Scholar 

  46. Houde N, Chamoux E, Bisson M, Roux S. Transforming growth factor-β1 (TGF-β1) induces human osteoclast apoptosis by up-regulating bim. J Biol Chem. 2009;284:23397–404.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. • Dole NS, Mazur CM, Acevedo C, Lopez JP, Monteiro DA, Fowler TW, Gludovatz B, Walsh F, Regan JN, Messina S, Evans DS, Lang TF, Zhang B, Ritchie RO, Mohammad KS, Alliston T. Osteocyte-intrinsic TGF-β signaling regulates bone quality through perilacunar/canalicular remodeling. Cell Rep. 2017;21:2585–96. (This research article showcases TGFβ as a key regulator of perilacunar/canalicular remodeling.)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. • Dole NS, Yee CS, Mazur CM, Acevedo C, Alliston T. TGFβ regulation of perilacunar/canalicular remodeling is sexually dimorphic. J Bone Miner Res. 2020;35:1549–61. (This paper highlights the link between TGFβ signaling and osteocytic perilacunar/canalicular remodeling during lactation.)

    Article  CAS  PubMed  Google Scholar 

  49. Schurman CA, Verbruggen SW, Alliston T. Disrupted osteocyte connectivity and pericellular fluid flow in bone with aging and defective TGF-β signaling. Proc Natl Acad Sci USA. 2021;118:e2023999118.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. • Bailey KN, Nguyen J, Yee CS, Dole NS, Dang A, Alliston T. Mechanosensitive control of articular cartilage and subchondral bone homeostasis in mice requires osteocytic transforming growth factor β signaling. Arthritis Rheumatol. 2021;73:414–25. (This research article demonstrates that osteocytic TGFβ signaling is required for subchondral bone mechanosensation and its subsequent regulation of sclerostin.)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Dole NS, Yoon J, Monteiro DA, Yang J, Mazur CM, Kaya S, Belair CD, Alliston T. Mechanosensitive miR-100 coordinates TGFβ and Wnt signaling in osteocytes during fluid shear stress. FASEB J. 2021;35:e21883.

    Article  CAS  PubMed  Google Scholar 

  52. • Liu W, Zhang D, Li X, Zheng L, Cui C, Cui Y, Sun J, Xie J, Zhou X. TGF-β1 facilitates cell–cell communication in osteocytes via connexin43- and pannexin1-dependent gap junctions. Cell Death Discov. 2019;5:141. (This research article chronicles the regulation of Cx43 and Panx1 by osteocytic TGFβ.)

    Article  PubMed  PubMed Central  Google Scholar 

  53. Dole NS, Yee C, Alliston T. Osteocyte-specific TGFβ signaling mitigates obesity-induced deregulated energy metabolism and compromised bone quality. J Endocr Soc. 2021;5:A441–2.

    Article  PubMed Central  Google Scholar 

  54. Fowler TW, Acevedo C, Mazur CM, Hall-Glenn F, Fields AJ, Bale HA, Ritchie RO, Lotz JC, Vail TP, Alliston T. Glucocorticoid suppression of osteocyte perilacunar remodeling is associated with subchondral bone degeneration in osteonecrosis. Sci Rep. 2017;7:44618.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Kerschnitzki M, Kollmannsberger P, Burghammer M, Duda GN, Weinkamer R, Wagermaier W, Fratzl P. Architecture of the osteocyte network correlates with bone material quality. J Bone Miner Res. 2013;28:1837–45.

    Article  CAS  PubMed  Google Scholar 

  56. Arnett TR. Osteocytes: regulating the mineral reserves? J Bone Miner Res. 2013;28:2433–5.

    Article  CAS  PubMed  Google Scholar 

  57. Qing H, Bonewald LF. Osteocyte remodeling of the perilacunar and pericanalicular matrix. Int J Oral Sci. 2009;1:59–65.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Inoue K, Mikuni-Takagaki Y, Oikawa K, Itoh T, Inada M, Noguchi T, Park JS, Onodera T, Krane SM, Noda M, Itohara S. A crucial role for matrix metalloproteinase 2 in osteocytic canalicular formation and bone metabolism. J Biol Chem. 2006;281:33814–24.

    Article  CAS  PubMed  Google Scholar 

  59. Holmbeck K, Bianco P, Pidoux I, Inoue S, Billinghurst RC, Wu W, Chrysovergis K, Yamada S, Birkedal-Hansen H, Poole AR. The metalloproteinase MT1-MMP is required for normal development and maintenance of osteocyte processes in bone. J Cell Sci. 2005;118:147–56.

    Article  CAS  PubMed  Google Scholar 

  60. Kulkarni RN, Bakker AD, Gruber EV, Chae TD, Veldkamp JBB, Klein-Nulend J, Everts V. MT1-MMP modulates the mechanosensitivity of osteocytes. Biochem Biophys Res Commun. 2012;417:824–9.

    Article  CAS  PubMed  Google Scholar 

  61. Kaya S, Basta-Pljakic J, Seref-Ferlengez Z, Majeska RJ, Cardoso L, Bromage TG, Zhang Q, Flach CR, Mendelsohn R, Yakar S, Fritton SP, Schaffler MB. Lactation-induced changes in the volume of osteocyte lacunar-canalicular space alter mechanical properties in cortical bone tissue. J Bone Miner Res. 2017;32:688–97.

    Article  CAS  PubMed  Google Scholar 

  62. Kegelman CD, Coulombe JC, Jordan KM, Horan DJ, Qin L, Robling AG, Ferguson VL, Bellido TM, Boerckel JD. YAP and TAZ mediate osteocyte perilacunar/canalicular remodeling. J Bone Miner Res. 2020;35:196–210.

    Article  CAS  PubMed  Google Scholar 

  63. • Nguyen J, Tang SY, Nguyen D, Alliston T. Load regulates bone formation and sclerostin expression through a TGFβ-dependent mechanism. PLoS ONE. 2013;8: e53813. (This research article investigates the role of TGFβ in regulating sclerostin and load-induced bone formation.)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Sahbani K, Cardozo CP, Bauman WA, Tawfeek HA. Inhibition of TGF-β signaling attenuates disuse-induced trabecular bone loss after spinal cord injury in male mice. Endocrinology 2022:163.

  65. Yu Z, Li Y, Wang Y, Chen Y, Wu M, Wang Z, Song M, Lu F, Lu X, Dong Z. TGF-β prevents the denervation-induced reduction of bone formation and promotes the bone regeneration through inhibiting ubiquitin-proteasome pathway. Biosci Rep 2019:39.

  66. Li Y, Jie L, Tian AY, Zhong S, Tian MY, Zhong Y, Wang Y, Li H, Li J, Sun X, Du H. Transforming growth factor beta is regulated by a glucocorticoid-dependent mechanism in denervation mouse bone. Sci Rep. 2017;7:9925.

    Article  PubMed  PubMed Central  Google Scholar 

  67. • Loots GG, Keller H, Leupin O, Murugesh D, Collette NM, Genetos DC. TGF-β regulates sclerostin expression via the ECR5 enhancer. Bone. 2012;50:663–9. (This paper establishes a key target of TGFβ used to enhance sclerostin.)

    Article  CAS  PubMed  Google Scholar 

  68. Aguilar-Perez A, Pacheco-Costa R, Atkinson EG, Deosthale P, Davis HM, Essex AL, Dilley JE, Gomez L, Rupert JE, Zimmers TA, Thompson RJ, Allen MR, Plotkin LI. Age- and sex-dependent role of osteocytic pannexin1 on bone and muscle mass and strength. Sci Rep. 2019;9:13903.

    Article  PubMed  PubMed Central  Google Scholar 

  69. Plotkin LI, Speacht TL, Donahue HJ. Cx43 and mechanotransduction in bone. Curr Osteoporos Rep. 2015;13:67–72.

    Article  PubMed  PubMed Central  Google Scholar 

  70. Rath Bonivtch A, Bonewald LF, Nicolella DP. Tissue strain amplification at the osteocyte lacuna: a microstructural finite element analysis. J Biomech. 2007;40:2199–206.

    Article  Google Scholar 

  71. Miller SC, Bowman BM. Rapid inactivation and apoptosis of osteoclasts in the maternal skeleton during the bone remodeling reversal at the end of lactation. Anat Rec. 2007;290:65–73.

    Article  CAS  Google Scholar 

  72. Agoro R, Ni P, Noonan ML, White KE. Osteocytic FGF23 and its kidney function. Front Endocrinol 2020:11.

  73. Kovacs CS. Maternal mineral and bone metabolism during pregnancy, lactation, and post-weaning recovery. Physiol Rev. 2016;96:449–547.

    Article  CAS  PubMed  Google Scholar 

  74. Ardeshirpour L, Dumitru C, Dann P, Sterpka J, VanHouten J, Kim W, Kostenuik P, Wysolmerski J. OPG treatment prevents bone loss during lactation but does not affect milk production or maternal calcium metabolism. Endocrinology. 2015;156:2762–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Powell WF, Barry KJ, Tulum I, Kobayashi T, Harris SE, Bringhurst FR, Divieti PP. Targeted ablation of the PTH/PTHrP receptor in osteocytes impairs bone structure and homeostatic calcemic responses. J Endocrinol. 2011;209:21–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Feger M, Hase P, Zhang B, Hirche F, Glosse P, Lang F, Föller M. The production of fibroblast growth factor 23 is controlled by TGF-β2. Sci Rep. 2017;7:4982.

    Article  PubMed  PubMed Central  Google Scholar 

  77. Subramaniam N, Leong GM, Cock T-A, Flanagan JL, Fong C, Eisman JA, Kouzmenko AP. Cross-talk between 1,25-dihydroxyvitamin D3 and transforming growth factor-β signaling requires binding of VDR and Smad3 proteins to their cognate DNA recognition elements. J Biol Chem. 2001;276:15741–6.

    Article  CAS  PubMed  Google Scholar 

  78. Fiz C, Apprato G, Ricca C, Aillon A, Bergandi L, Silvagno F. TGF beta induces vitamin D receptor and modulates mitochondrial activity of human pancreatic cancer cells. Cancers. 2021;13:2932.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Wang F, Chang H-M, Yi Y, Lin Y-M, Li H, Leung PCK. TGF-β1 promotes vitamin D-induced prostaglandin E2 synthesis by upregulating vitamin D receptor expression in human granulosa-lutein cells. Am J Physiol Endocrinol. 2020;318:E710–22.

    Article  CAS  Google Scholar 

  80. Iwasaki Y, Yamato H, Fukagawa M. TGF-beta signaling in bone with chronic kidney disease. Int J Mol Sci. 2018;19:2352.

    Article  PubMed  PubMed Central  Google Scholar 

  81. Iwasaki-Ishizuka Y, Yamato H, Nii-Kono T, Kurokawa K, Fukagawa M. Downregulation of parathyroid hormone receptor gene expression and osteoblastic dysfunction associated with skeletal resistance to parathyroid hormone in a rat model of renal failure with low turnover bone. Nephrol Dial Transplant. 2005;20:1904–11.

    Article  CAS  PubMed  Google Scholar 

  82. Evenepoel P, Bover J, Ureña TP. Parathyroid hormone metabolism and signaling in health and chronic kidney disease. Kidney Int. 2016;90:1184–90.

    Article  CAS  PubMed  Google Scholar 

  83. Jongen JW, Willemstein-Van Hove EC, Van der Meer JM, Bos MP, Jüppner H, Segre GV, Abou-Samra AB, Feyen JH, Herrmann-Erlee MP. Down-regulation of the receptor for parathyroid hormone (PTH) and PTH-related peptide by transforming growth factor-beta in primary fetal rat osteoblasts. Endocrinology. 1995;136:3260–6.

    Article  CAS  PubMed  Google Scholar 

  84. Wesseling-Perry K. Osteocyte dysfunction and renal osteodystrophy: not just calcium and phosphorus anymore. Kidney Int. 2017;91:1276–8.

    Article  CAS  PubMed  Google Scholar 

  85. Dussold C, Gerber C, White S, Wang X, Qi L, Francis C, Capella M, Courbon G, Wang J, Li C, Feng JQ, Isakova T, Wolf M, David V, Martin A. DMP1 prevents osteocyte alterations, FGF23 elevation and left ventricular hypertrophy in mice with chronic kidney disease. Bone Res. 2019;7:12.

    Article  PubMed  PubMed Central  Google Scholar 

  86. Agoro R, Nookaew I, Noonan ML, Marambio YG, Liu S, Chang W, Gao H, Hibbard LM, Metzger CE, Horan D, Thompson WR, Xuei X, Liu Y, Zhang C, Robling AG, Bonewald LF, Wan J, White KE. Single cell cortical bone transcriptomics define novel osteolineage gene sets altered in chronic kidney disease. Front Endocrinol 2023:14.

  87. Karthik V, Guntur AR. Energy metabolism of osteocytes. Curr Osteoporos Rep. 2021;19:444–51.

    Article  PubMed  PubMed Central  Google Scholar 

  88. Wang C, Silverman RM, Shen J, O’Keefe RJ. Distinct metabolic programs induced by TGF-β1 and BMP2 in human articular chondrocytes with osteoarthritis. J Orthop Translat. 2018;12:66–73.

    Article  PubMed  PubMed Central  Google Scholar 

  89. Song C, Long F. 2022. Glucose metabolism is essential for TGFβ mediated joint development. J Bone Miner Res 38 (Suppl 1). Available at https://www.asbmr.org/education/AbstractDetail?aid=f0c62847-9804-4337-86d2-2ddeb8a761e6. Accessed September 12, 2022.

  90. Kitagawa T, Masumi A, Akamatsu Y. Transforming growth factor-beta 1 stimulates glucose uptake and the expression of glucose transporter mRNA in quiescent Swiss mouse 3T3 cells. J Biol Chem. 1991;266:18066–71.

    Article  CAS  PubMed  Google Scholar 

  91. Yin X, Choudhury M, Kang J-H, Schaefbauer KJ, Jung M-Y, Andrianifahanana M, Hernandez DM, Leof EB. Hexokinase 2 couples glycolysis with the profibrotic actions of TGF-β. Sci Signal. 2019;12:eaax4067.

    Article  CAS  PubMed  Google Scholar 

  92. Inoki K, Haneda M, Maeda S, Koya D, Kikkawa R. TGF-β1 stimulates glucose uptake by enhancing GLUT1 expression in mesangial cells. Kidney Int. 1999;55:1704–12.

    Article  CAS  PubMed  Google Scholar 

  93. Jin J, Bakker AD, Wu G, Klein-Nulend J, Jaspers RT. Physicochemical niche conditions and mechanosensing by osteocytes and myocytes. Curr Osteoporos Rep. 2019;17:235–49.

    Article  PubMed  PubMed Central  Google Scholar 

  94. Yellowley CE, Genetos DC. Hypoxia signaling in the skeleton: implications for bone health. Curr Osteoporos Rep. 2019;17:26–35.

    Article  PubMed  PubMed Central  Google Scholar 

  95. Chen K, Zhao J, Qiu M, Zhang L, Yang K, Chang L, Jia P, Qi J, Deng L, Li C. Osteocytic HIF-1α pathway manipulates bone micro-structure and remodeling via regulating osteocyte terminal differentiation. Front Cell Dev Biol 2022:9.

  96. Guntur AR, Gerencser AA, Le PT, DeMambro VE, Bornstein SA, Mookerjee SA, Maridas DE, Clemmons DE, Brand MD, Rosen CJ. Osteoblast-like MC3T3-E1 cells prefer glycolysis for ATP production but adipocyte-like 3T3-L1 cells prefer oxidative phosphorylation. J Bone Miner Res. 2018;33:1052–65.

    Article  CAS  PubMed  Google Scholar 

  97. Karner CM, Long F. Wnt signaling and cellular metabolism in osteoblasts. Cell Mol Life Sci. 2017;74:1649–57.

    Article  CAS  PubMed  Google Scholar 

  98. Karner CM, Long F. Glucose metabolism in bone. Bone. 2018;115:2–7.

    Article  CAS  PubMed  Google Scholar 

  99. Li B, Lee W, Song C, Ye L, Abel ED, Long F. Both aerobic glycolysis and mitochondrial respiration are required for osteoclast differentiation. FASEB J. 2020;34:11058–67.

    Article  CAS  PubMed  Google Scholar 

  100. Dole NS, Kaya S, Yee C, Yoon C, Salinas J, Miclau E, Alliston T. 2021. Ablating osteocytic TGFβ signaling mitigates the effects of obesity on systemic energy balance and bone quality. J Bone Miner Res 37 (Suppl 1). Available at https://www.asbmr.org/meetings/annualmeeting/AbstractDetail?aid=3b72065a-4732-4b1e-aac4-4f5217504e2f. Accessed October 4, 2021.

  101. Trivedi T, Bahrami A, John S, Suresh S, Murthy S, Pagnotti G, She Y, Cao X, Mohammad K, Guise T. 2021.Excess TGFβ together with high fat diet exacerbates bone destruction and altered fat metabolism in mice with high bone turnover. J Bone Miner Res 37 (Suppl 1). Available at https://www.asbmr.org/meetings/annualmeeting/AbstractDetail?aid=02afb89c-1530-49fb-b186-681eb64fdacd. Accessed October 3, 2021.

  102. Baek K, Hwang HR, Park H-J, Kwon A, Qadir AS, Ko S-H, Woo KM, Ryoo H-M, Kim G-S, Baek J-H. TNF-α upregulates sclerostin expression in obese mice fed a high-fat diet. J Cell Physiol. 2014;229:640–50.

    Article  CAS  PubMed  Google Scholar 

  103. Kim SP, Frey JL, Li Z, Kushwaha P, Zoch ML, Tomlinson RE, Da H, Aja S, Noh HL, Kim JK, Hussain MA, Thorek DLJ, Wolfgang MJ, Riddle RC. Sclerostin influences body composition by regulating catabolic and anabolic metabolism in adipocytes. Proc Natl Acad Sci USA. 2017;114:E11238–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Riddle RC. Endocrine functions of sclerostin. Curr Opin Endocr Metab Res. 2023;28:100433.

    Article  CAS  Google Scholar 

  105. Regan JN, Trivedi T, Guise TA, Waning DL. The role of TGFβ in bone-muscle crosstalk. Curr Osteoporos Rep. 2017;15:18–23.

    Article  PubMed  PubMed Central  Google Scholar 

  106. Zhou B, Zhang Q, Lin X, Hu J, Zhao D, Jiang Y, Xing X, Li M. The roles of sclerostin and irisin on bone and muscle of orchiectomized rats. BMC Musculoskelet Disord. 2022;23:1049.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Magarò MS, Bertacchini J, Florio F, Zavatti M, Potì F, Cavani F, Amore E, De Santis I, Bevilacqua A, Reggiani Bonetti L, Torricelli P, Maurel DB, Biressi S, Palumbo C. Identification of sclerostin as a putative new myokine involved in the muscle-to-bone crosstalk. Biomedicines. 2021;9:71.

    Article  PubMed  PubMed Central  Google Scholar 

  108. Waning DL, Mohammad KS, Reiken S, Xie W, Andersson DC, John S, Chiechi A, Wright LE, Umanskaya A, Niewolna M, Trivedi T, Charkhzarrin S, Khatiwada P, Wronska A, Haynes A, Benassi MS, Witzmann FA, Zhen G, Wang X, Cao X, Roodman GD, Marks AR, Guise TA. Excess TGF-β mediates muscle weakness associated with bone metastases in mice. Nat Med. 2015;21:1262–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Li G, Zhang L, Lu Z, Yang B, Yang H, Shang P, Jiang JX, Wang D, Xu H. Connexin 43 channels in osteocytes are necessary for bone mass and skeletal muscle function in aged male mice. Int J Mol Sci. 2022;23:13506.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Gencer S, Oleinik N, Kim J, Panneer Selvam S, De Palma R, Dany M, Nganga R, Thomas RJ, Senkal CE, Howe PH, Ogretmen B. TGF-β receptor I/II trafficking and signaling at primary cilia are inhibited by ceramide to attenuate cell migration and tumor metastasis. Sci Signal. 2017;24:10.

    Google Scholar 

  111. Liu S, Hou H, Zhang P, Wu Y, He X, Li H, Yan N. Sphingomyelin synthase 1 regulates the epithelial-to-mesenchymal transition mediated by the TGF-β/Smad pathway in MDA-MB-231 cells. Mol Med Rep. 2019;19:1159–67.

    CAS  PubMed  Google Scholar 

  112. Liu H, Chen YG. The interplay between TGF-β signaling and cell metabolism. Front Cell Dev Biol. 2022;9(10):846723.

    Article  Google Scholar 

  113. Chen M, Zhao Y, Yang X, Zhao Y, Liu Q, Liu Y, Hou Y, Sun H, Jin W. NSDHL promotes triple-negative breast cancer metastasis through the TGFβ signaling pathway and cholesterol biosynthesis. Breast Cancer Res Treat. 2021;187:349–62.

    Article  CAS  PubMed  Google Scholar 

  114. Vasiukov G, Novitskaya T, Zijlstra A, Owens P, Ye F, Zhao Z, Moses HL, Blackwell T, Feoktistov I, Novitskiy SV. Myeloid cell-derived TGFβ signaling regulates ECM deposition in mammary carcinoma via adenosine-dependent mechanisms. Cancer Res. 2020;80:2628–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Fan J, Jahed V, Klavins K. Metabolomics in Bone Research. Metabolites. 2021;11:434.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Miyamoto T, Hirayama A, Sato Y, Koboyashi T, Katsuyama E, Kanagawa H, Fujie A, Morita M, Watanabe R, Tando T, Miyamoto K, Tsuji T, Funayama A, Soga T, Tomita M, Nakamura M, Matsumoto M. Metabolomics-based profiles predictive of low bone mass in menopausal women. Bone Rep. 2018;9:11–8.

    Article  PubMed  PubMed Central  Google Scholar 

  117. Galvez-Fernandez M, Rodriguez-Hernandez Z, Grau-Perez M, Chaves FJ, Garcia-Garcia AB, Amigo N, Monleon D, Garcia-Barrera T, Gomez-Ariza JL, Briongos-Figuero LS, Perez-Castrillon JL, Redon J, Tellez-Plaza M, Martin-Escudero JC. Metabolomic patterns, redox-related genes and metals, and bone fragility endpoints in the Hortega Study. Free Radic Biol Med. 2023;194:52–61.

    Article  CAS  PubMed  Google Scholar 

  118. Collette NM, Genetos DC, Economides AN, Xie L, Shahnazari M, Yao W, Lane NE, Harland RM, Loots GG. Targeted deletion of Sost distal enhancer increases bone formation and bone mass. Proc Natl Acad Sci USA. 2012;109:14092–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Holguin N, Brodt MD, Silva MJ. Activation of Wnt signaling by mechanical loading is impaired in the bone of old mice. J Bone Miner Res. 2016;31:2215–26.

    Article  CAS  PubMed  Google Scholar 

  120. Aryana IGPS, Rini SS, Soejono CH. Importance of sclerostin as bone-muscle mediator crosstalk. Ann Geriatr Med Res. 2022;26:72–82.

    Article  PubMed  PubMed Central  Google Scholar 

  121. Huang J, Romero-Suarez S, Lara N, Mo C, Kaja S, Brotto L, Dallas SL, Johnson ML, Jähn K, Bonewald LF, Brotto M. Crosstalk between MLO-Y4 osteocytes and C2C12 muscle cells is mediated by the Wnt/β-catenin pathway. JBMR Plus. 2017;1:86–100.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Kim JA, Roh E, Hong SH, Lee YB, Kim NH, Yoo HJ, Seo JA, Kim NH, Kim SG, Baik S-H, Choi KM. Association of serum sclerostin levels with low skeletal muscle mass: the Korean sarcopenic obesity study (KSOS). Bone. 2019;128:115053.

    Article  CAS  PubMed  Google Scholar 

  123. O’Brien CA, Plotkin LI, Galli C, Goellner JJ, Gortazar AR, Allen MR, Robling AG, Bouxsein M, Schipani E, Turner CH, Jilka RL, Weinstein RS, Manolagas SC, Bellido T. Control of bone mass and remodeling by PTH receptor signaling in osteocytes. PLoS ONE. 2008;3:e2942.

    Article  PubMed  PubMed Central  Google Scholar 

  124. Qiu T, Crane JL, Xie L, Xian L, Xie H, Cao X. IGF-I induced phosphorylation of PTH receptor enhances osteoblast to osteocyte transition. Bone Res. 2018;6:5.

    Article  PubMed  PubMed Central  Google Scholar 

  125. Delgado-Calle J, Tu X, Pacheco-Costa R, McAndrews K, Edwards R, Pellegrini GG, Kuhlenschmidt K, Olivos N, Robling A, Peacock M, Plotkin LI, Bellido T. Control of bone anabolism in response to mechanical loading and pth by distinct mechanisms downstream of the PTH receptor. J Bone Miner Res. 2017;32:522–35.

    Article  CAS  PubMed  Google Scholar 

  126. Rhee Y, Allen MR, Condon K, Lezcano V, Ronda AC, Galli C, Olivos N, Passeri G, O’Brien CA, Bivi N, Plotkin LI, Bellido T. PTH receptor signaling in osteocytes governs periosteal bone formation and intracortical remodeling. J Bone Miner Res. 2011;26:1035–46.

    Article  CAS  PubMed  Google Scholar 

  127. Uda Y, Saini V, Petty CA, Alshehri M, Shi C, Spatz JM, Santos R, Newell CM, Huang TY, Kochen A, Kim JW, Constantinou CK, Saito H, Held KD, Hesse E, Pajevic PD. Parathyroid hormone signaling in mature osteoblasts/osteocytes protects mice from age-related bone loss. Aging. 2021;13:25607–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Fan Y, Bi R, Densmore MJ, Sato T, Kobayashi T, Yuan Q, Zhou X, Erben RG, Lanske B. Parathyroid hormone 1 receptor is essential to induce FGF23 production and maintain systemic mineral ion homeostasis. FASEB J. 2016;30:428–40.

    Article  CAS  PubMed  Google Scholar 

  129. Zarka M, Etienne F, Bourmaud M, Szondi D, Schwartz J-M, Kampmann K, Helary C, Rannou F, Haÿ E, Cohen-Solal M. Mechanical loading activates the YAP/TAZ pathway and chemokine expression in the MLO-Y4 osteocyte-like cell line. Lab Invest. 2021;101:1597–604.

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This work was supported by the Arkansas Biosciences Institute (AWD55316, NSD), NIH-NIDDK K01 (DK129404, NSD), NIH/NIGMS (1P20GM125503, NSD), the UAMS Musculoskeletal Creative Hub Pilot Award (NSD), NIH-NIDCR R01 (DE019284, TA), and NIH-NIAMS P30 (AR075055, TA).

Author information

Authors and Affiliations

  1. Department of Physiology and Cell Biology, University of Arkansas for Medical Sciences, Little Rock, AR, USA

    M. Carroll & N. Dole

  2. Department of Orthopaedic Surgery, University of California, San Francisco, San Francisco, CA, USA

    T. Alliston

  3. Department of Orthopaedic Surgery, University of Arkansas for Medical Sciences, Little Rock, AR, USA

    N. Dole

Authors
  1. M. Carroll
    View author publications

    Search author on:PubMed Google Scholar

  2. T. Alliston
    View author publications

    Search author on:PubMed Google Scholar

  3. N. Dole
    View author publications

    Search author on:PubMed Google Scholar

Corresponding author

Correspondence to N. Dole.

Ethics declarations

Conflict of Interest

The authors have no conflicts of interest to disclose.

Human and Animal Rights and Informed Consent

All reported studies/experiments with human or animal subjects performed by the authors have been previously published and complied with all applicable ethical standards (including the Helsinki Declaration and its amendments, institutional/national research committee standards, and international/national/institutional guidelines).

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Carroll, M., Alliston, T. & Dole, N. The Multifaceted Effects of Osteocytic TGFβ Signaling on the Skeletal and Extraskeletal Functions of Bone. Curr Osteoporos Rep 21, 414–425 (2023). https://doi.org/10.1007/s11914-023-00802-w

Download citation

  • Accepted:

  • Published:

  • Version of record:

  • Issue date:

  • DOI: https://doi.org/10.1007/s11914-023-00802-w

Keywords

Profiles

  1. N. Dole View author profile