Skip to main content

Advertisement

SpringerLink
Log in

PGC-1: a key regulator in bone homeostasis

  • Review Article
  • Published:
Journal of Bone and Mineral Metabolism Aims and scope Submit manuscript

Abstract

Peroxisome proliferator-activated receptor-γ coactivator-1 (PGC-1) is an inducible co-regulator of nuclear receptors and is involved in a wide variety of biological responses. As the master regulators of mitochondrial biogenesis and function, PGC-1α and PGC-1β have been reported to play key roles in bone metabolism. They can be rapidly induced under conditions of increased metabolic activities, such as osteoblastogenesis and osteoclastogenesis, to fulfill greater energy demand or facilitate other biochemical reactions. PGC-1α and PGC-1β have both overlapping and distinct functions with each other among their target organs. In bone homeostasis, PGC-1α and PGC-1β promote the expression of genes required for mitochondrial biogenesis via coactivator interactions with key transcription factors, respectively regulating osteoblastogenesis and osteoclastogenesis. Here, we review the current understanding of how PGC-1α and PGC-1β affect osteoblastogenesis and osteoclastogenesis, how these two PGC-1 coactivators are regulated in bone homeostasis, and how we can translate these findings into therapeutic potential for bone metabolic diseases.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Finck BN, Kelly DP (2006) PGC-1 coactivators: inducible regulators of energy metabolism in health and disease. J Clin Invest 116:615–622

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. Liu C, Lin JD (2011) PGC-1 coactivators in the control of energy metabolism. Acta Biochim Biophys Sin (Shanghai) 43:248–257

    Article  CAS  Google Scholar 

  3. Andersson U, Scarpulla RC (2001) Pgc-1-related coactivator, a novel, serum-inducible coactivator of nuclear respiratory factor 1-dependent transcription in mammalian cells. Mol Cell Biol 21:3738–3749

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Zheng CX, Sui BD, Qiu XY, Hu CH, Jin Y (2020) Mitochondrial regulation of stem cells in bone homeostasis. Trends Mol Med 26:89–104

    Article  PubMed  CAS  Google Scholar 

  5. Feng X, McDonald JM (2011) Disorders of bone remodeling. Annu Rev Pathol 6:121–145

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Ishii KA, Fumoto T, Iwai K, Takeshita S, Ito M, Shimohata N, Aburatani H, Taketani S, Lelliott CJ, Vidal-Puig A, Ikeda K (2009) Coordination of PGC-1beta and iron uptake in mitochondrial biogenesis and osteoclast activation. Nat Med 15:259–266

    Article  PubMed  CAS  Google Scholar 

  7. Colaianni G, Lippo L, Sanesi L, Brunetti G, Celi M, Cirulli N, Passeri G, Reseland J, Schipani E, Faienza MF, Tarantino U, Colucci S, Grano M (2018) Deletion of the transcription factor PGC-1alpha in mice negatively regulates bone mass. Calcif Tissue Int 103:638–652

    Article  PubMed  CAS  Google Scholar 

  8. Scarpulla RC (2011) Metabolic control of mitochondrial biogenesis through the PGC-1 family regulatory network. Biochim Biophys Acta 1813:1269–1278

    Article  PubMed  CAS  Google Scholar 

  9. Wu Z, Puigserver P, Andersson U, Zhang C, Adelmant G, Mootha V, Troy A, Cinti S, Lowell B, Scarpulla RC, Spiegelman BM (1999) Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1. Cell 98:115–124

    Article  PubMed  CAS  Google Scholar 

  10. Yu B, Huo L, Liu Y, Deng P, Szymanski J, Li J, Luo X, Hong C, Lin J, Wang CY (2018) PGC-1alpha controls skeletal stem cell fate and bone-fat balance in osteoporosis and skeletal aging by inducing TAZ. Cell Stem Cell 23:193-209.e195

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Uldry M, Yang W, St-Pierre J, Lin J, Seale P, Spiegelman BM (2006) Complementary action of the PGC-1 coactivators in mitochondrial biogenesis and brown fat differentiation. Cell Metab 3:333–341

    Article  PubMed  CAS  Google Scholar 

  12. Yang D, Wan Y (2019) Molecular determinants for the polarization of macrophage and osteoclast. Semin Immunopathol 41:551–563

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, Moorman MA, Simonetti DW, Craig S, Marshak DR (1999) Multilineage potential of adult human mesenchymal stem cells. Science 284:143–147

    Article  PubMed  CAS  Google Scholar 

  14. Lee AR, Moon DK, Siregar A, Moon SY, Jeon RH, Son YB, Kim BG, Hah YS, Hwang SC, Byun JH, Woo DK (2019) Involvement of mitochondrial biogenesis during the differentiation of human periosteum-derived mesenchymal stem cells into adipocytes, chondrocytes and osteocytes. Arch Pharm Res 42:1052–1062

    Article  PubMed  CAS  Google Scholar 

  15. Hsu YC, Wu YT, Yu TH, Wei YH (2016) Mitochondria in mesenchymal stem cell biology and cell therapy: from cellular differentiation to mitochondrial transfer. Semin Cell Dev Biol 52:119–131

    Article  PubMed  CAS  Google Scholar 

  16. Chen CT, Shih YR, Kuo TK, Lee OK, Wei YH (2008) Coordinated changes of mitochondrial biogenesis and antioxidant enzymes during osteogenic differentiation of human mesenchymal stem cells. Stem Cells 26:960–968

    Article  PubMed  CAS  Google Scholar 

  17. Handschin C (2009) The biology of PGC-1alpha and its therapeutic potential. Trends Pharmacol Sci 30:322–329

    Article  PubMed  CAS  Google Scholar 

  18. Sanchez-de-Diego C, Artigas N, Pimenta-Lopes C, Valer JA, Torrejon B, Gama-Perez P, Villena JA, Garcia-Roves PM, Rosa JL, Ventura F (2019) Glucose restriction promotes osteocyte specification by activating a PGC-1alpha-dependent transcriptional program. J Physiol 15:79–94

    CAS  Google Scholar 

  19. Huang PI, Chou YC, Chang YL, Chien Y, Chen KH, Song WS, Peng CH, Chang CH, Lee SD, Lu KH, Chen YJ, Kuo CH, Hsu CC, Lee HC, Yung MC (2011) Enhanced differentiation of three-gene-reprogrammed induced pluripotent stem cells into adipocytes via adenoviral-mediated PGC-1alpha overexpression. Int J Mol Sci 12:7554–7568

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Park-Min KH (2018) Mechanisms involved in normal and pathological osteoclastogenesis. Cell Mol Life Sci 75:2519–2528

    Article  PubMed  CAS  Google Scholar 

  21. Lucas S, Omata Y, Hofmann J, Bottcher M, Iljazovic A, Sarter K, Albrecht O, Schulz O, Krishnacoumar B, Kronke G, Herrmann M, Mougiakakos D, Strowig T, Schett G, Zaiss MM (2018) Short-chain fatty acids regulate systemic bone mass and protect from pathological bone loss. Nat Commun 9:55

    Article  PubMed  PubMed Central  Google Scholar 

  22. Lelliott CJ, Medina-Gomez G, Petrovic N, Kis A, Feldmann HM et al (2006) Ablation of PGC-1beta results in defective mitochondrial activity, thermogenesis, hepatic function, and cardiac performance. PLoS Biol 4:e369

    Article  PubMed  PubMed Central  Google Scholar 

  23. Ma JD, Jing J, Wang JW, Mo YQ, Li QH, Lin JZ, Chen LF, Shao L, Miossec P, Dai L (2019) Activation of the peroxisome proliferator-activated receptor gamma coactivator 1beta/NFATc1 pathway in circulating osteoclast precursors associated with bone destruction in rheumatoid arthritis. Arthritis Rheumatol 71:1252–1264

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Lin J, Handschin C, Spiegelman BM (2005) Metabolic control through the PGC-1 family of transcription coactivators. Cell Metab 1:361–370

    Article  PubMed  Google Scholar 

  25. Lin J, Puigserver P, Donovan J, Tarr P, Spiegelman BM (2002) Peroxisome proliferator-activated receptor gamma coactivator 1beta (PGC-1beta), a novel PGC-1-related transcription coactivator associated with host cell factor. J Biol Chem 277:1645–1648

    Article  PubMed  CAS  Google Scholar 

  26. Ventura-Clapier R, Garnier A, Veksler V (2008) Transcriptional control of mitochondrial biogenesis: the central role of PGC-1alpha. Cardiovasc Res 79:208–217

    Article  PubMed  CAS  Google Scholar 

  27. Zaccagnino P, Saltarella M, Maiorano S, Gaballo A, Santoro G, Nico B, Lorusso M, Del Prete A (2012) An active mitochondrial biogenesis occurs during dendritic cell differentiation. Int J Biochem Cell Biol 44:1962–1969

    Article  PubMed  CAS  Google Scholar 

  28. Xing W, Singgih A, Kapoor A, Alarcon CM, Baylink DJ, Mohan S (2007) Nuclear factor-E2-related factor-1 mediates ascorbic acid induction of osterix expression via interaction with antioxidant-responsive element in bone cells. J Biol Chem 282:22052–22061

    Article  PubMed  CAS  Google Scholar 

  29. Jiang LL, Zhang FP, He YF, Fan WG, Zheng MM, Kang J, Huang F, He HW (2019) Melatonin regulates mitochondrial function and biogenesis during rat dental papilla cell differentiation. Eur Rev Med Pharmacol Sci 23:5967–5979

    PubMed  Google Scholar 

  30. Shen Y, Wu L, Qin D, Xia Y, Zhou Z, Zhang X (2018) Carbon black suppresses the osteogenesis of mesenchymal stem cells: the role of mitochondria. Part Fibre Toxicol 15:16

    Article  PubMed  PubMed Central  Google Scholar 

  31. Meirhaeghe A, Crowley V, Lenaghan C, Lelliott C, Green K, Stewart A, Hart K, Schinner S, Sethi JK, Yeo G, Brand MD, Cortright RN, O’Rahilly S, Montague C, Vidal-Puig AJ (2003) Characterization of the human, mouse and rat PGC1 beta (peroxisome-proliferator-activated receptor-gamma co-activator 1 beta) gene in vitro and in vivo. Biochem J 373:155–165

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Lin J, Tarr PT, Yang R, Rhee J, Puigserver P, Newgard CB, Spiegelman BM (2003) PGC-1beta in the regulation of hepatic glucose and energy metabolism. J Biol Chem 278:30843–30848

    Article  PubMed  CAS  Google Scholar 

  33. Wei W, Wang X, Yang M, Smith LC, Dechow PC, Sonoda J, Evans RM, Wan Y (2010) PGC1beta mediates PPARgamma activation of osteoclastogenesis and rosiglitazone-induced bone loss. Cell Metab 11:503–516

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Park UH, Yoon SK, Park T, Kim EJ, Um SJ (2011) Additional sex comb-like (ASXL) proteins 1 and 2 play opposite roles in adipogenesis via reciprocal regulation of peroxisome proliferator-activated receptor. J Biol Chem 286:1354–1363

    Article  PubMed  CAS  Google Scholar 

  35. Izawa T, Rohatgi N, Fukunaga T, Wang QT, Silva MJ, Gardner MJ, McDaniel ML, Abumrad NA, Semenkovich CF, Teitelbaum SL, Zou W (2015) ASXL2 regulates glucose, lipid, and skeletal homeostasis. Cell Rep 11:1625–1637

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Bonnelye E, Kung V, Laplace C, Galson DL, Aubin JE (2002) Estrogen receptor-related receptor alpha impinges on the estrogen axis in bone: potential function in osteoporosis. Endocrinology 143:3658–3670

    Article  PubMed  CAS  Google Scholar 

  37. Wang H, Wang J (2013) Estrogen-related receptor alpha interacts cooperatively with peroxisome proliferator-activated receptor-gamma coactivator-1alpha to regulate osteocalcin gene expression. Cell Biol Int 37:1259–1265

    PubMed  CAS  Google Scholar 

  38. Kammerer M, Gutzwiller S, Stauffer D, Delhon I, Seltenmeyer Y, Fournier B (2013) Estrogen Receptor alpha (ERalpha) and Estrogen Related Receptor alpha (ERRalpha) are both transcriptional regulators of the Runx2-I isoform. Mol Cell Endocrinol 369:150–160

    Article  PubMed  CAS  Google Scholar 

  39. Bonnelye E, Saltel F, Chabadel A, Zirngibl RA, Aubin JE, Jurdic P (2010) Involvement of the orphan nuclear estrogen receptor-related receptor alpha in osteoclast adhesion and transmigration. J Mol Endocrinol 45:365–377

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Kamei Y, Ohizumi H, Fujitani Y, Nemoto T, Tanaka T, Takahashi N, Kawada T, Miyoshi M, Ezaki O, Kakizuka A (2003) PPARgamma coactivator 1beta/ERR ligand 1 is an ERR protein ligand, whose expression induces a high-energy expenditure and antagonizes obesity. Proc Natl Acad Sci USA 100:12378–12383

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Epstein PM (2012) Bone and the cAMP signaling pathway: emerging therapeutics. In: Bronner F, Farach-Carson M, Roach H (eds) Bone-metabolic functions and modulators. Topics in Bone Biology, vol 7. Springer, London, pp 271–287

  42. Nervina JM, Magyar CE, Pirih FQ, Tetradis S (2006) PGC-1alpha is induced by parathyroid hormone and coactivates Nurr1-mediated promoter activity in osteoblasts. Bone 39:1018–1025

    Article  PubMed  CAS  Google Scholar 

  43. Blagodatski A, Klimenko A, Jia L, Katanaev VL (2020) Small molecule Wnt pathway modulators from natural sources: history, state of the art and perspectives. Cells 9:589

    Article  PubMed Central  CAS  Google Scholar 

  44. Maeda K, Kobayashi Y, Koide M, Uehara S, Okamoto M, Ishihara A, Kayama T, Saito M, Marumo K (2019) The regulation of bone metabolism and disorders by Wnt signaling. Int J Mol Sci 20:5525

    Article  PubMed Central  CAS  Google Scholar 

  45. An JH, Yang JY, Ahn BY, Cho SW, Jung JY, Cho HY, Cho YM, Kim SW, Park KS, Kim SY, Lee HK, Shin CS (2010) Enhanced mitochondrial biogenesis contributes to Wnt induced osteoblastic differentiation of C3H10T1/2 cells. Bone 47:140–150

    Article  PubMed  CAS  Google Scholar 

  46. Min W, Fang P, Huang G, Shi M, Zhang Z (2018) The decline of whole-body glucose metabolism in ovariectomized rats. Nat Commun 113:106–112

    CAS  Google Scholar 

  47. Zhou JJ, Ma JD, Mo YQ, Zheng DH, Chen LF, Wei XN, Dai L (2014) Down-regulating peroxisome proliferator-activated receptor-gamma coactivator-1 beta alleviates the proinflammatory effect of rheumatoid arthritis fibroblast-like synoviocytes through inhibiting extracellular signal-regulated kinase, p38 and nuclear factor-kappaB activation. Arthritis Res Ther 16:472

    Article  PubMed  PubMed Central  Google Scholar 

  48. Shapiro G, Fishleder J, Stepensky P, Simanovsky N, Goldman V, Lamdan R (2020) Skeletal changes following hematopoietic stem cell transplantation in osteopetrosis. J Bone Miner Res 35:1645–1651

    Article  PubMed  CAS  Google Scholar 

  49. Han X, Nonaka K, Kato H, Yamaza H, Sato H, Kifune T, Hirofuji Y, Masuda K (2019) Osteoblastic differentiation improved by bezafibrate-induced mitochondrial biogenesis in deciduous tooth-derived pulp stem cells from a child with Leigh syndrome. Biochem Biophys Rep 17:32–37

    PubMed  Google Scholar 

  50. Momken I, Stevens L, Bergouignan A, Desplanches D, Rudwill F, Chery I, Zahariev A, Zahn S, Stein TP, Sebedio JL, Pujos-Guillot E, Falempin M, Simon C, Coxam V, Andrianjafiniony T, Gauquelin-Koch G, Picquet F, Blanc S (2011) Resveratrol prevents the wasting disorders of mechanical unloading by acting as a physical exercise mimetic in the rat. Faseb J 25:3646–3660

    Article  PubMed  CAS  Google Scholar 

  51. Pal S, Maurya SK, Chattopadhyay S, Pal China S, Porwal K, Kulkarni C, Sanyal S, Sinha RA, Chattopadhyay N (2019) The osteogenic effect of liraglutide involves enhanced mitochondrial biogenesis in osteoblasts. Biochem Pharmacol 164:34–44

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. Deng T, Sieglaff DH, Zhang A, Lyon CJ, Ayers SD, Cvoro A, Gupte AA, Xia X, Baxter JD, Webb P, Hsueh WA (2011) A peroxisome proliferator-activated receptor gamma (PPARgamma)/PPARgamma coactivator 1beta autoregulatory loop in adipocyte mitochondrial function. J Biol Chem 286:30723–30731

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by the National Natural Science Foundation of China [grant numbers 81870737], Natural Science Foundation of Guangdong Province, China [grant numbers 2021A1515011779], Guangdong Financial Fund for High-Caliber Hospital Construction [grant numbers 174-2018-XMZC-0001-03-0125/D-02], and National Natural Science Foundation of China [grant numbers 81771098].

Author information

Authors and Affiliations

  1. Hospital of Stomatology, Sun Yat-Sen University, 56 Lingyuan Xi Road, Guangzhou, 510055, China

    Haoling Chen, Wenguo Fan & Fang Huang

  2. Guangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Sun Yat-Sen University, 74 Zhongshan Rd 2, Guangzhou, 510080, China

    Haoling Chen, Wenguo Fan, Hongwen He & Fang Huang

Authors
  1. Haoling Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Wenguo Fan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hongwen He
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Fang Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Hongwen He or Fang Huang.

Ethics declarations

Conflict of interest

The authors declare that there are no conflicts of interest regarding the publication of this paper.

Additional information

Publisher's Note

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

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chen, H., Fan, W., He, H. et al. PGC-1: a key regulator in bone homeostasis. J Bone Miner Metab 40, 1–8 (2022). https://doi.org/10.1007/s00774-021-01263-w

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00774-021-01263-w

Keywords

Search

Navigation