Skip to main content
SpringerLink
Log in

Effect of retinoic acid and vitamin D3 on osteoblast differentiation and activity in aging

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

Abstract

Several studies have evidenced that in aging, osteoblast functional activity is impaired: osteoblast proliferation is slower and matrix deposition is less efficient. Because peroxisome-proliferator-activated receptor γ2 (PPARγ2) and fatty acids are important inhibitory signals in osteoblast development, we have investigated in human primary osteoblasts obtained from patients of different ages, the influence of retinoic acid and calcitriol on enzymes involved in differentiative (PPARγ2, β-catenin, and insulin-like growth factor 1) and metabolic (carnitine palmitoyltransferase 1) intracellular pathways, and on transglutaminase 2, as enzyme fundamental for stabilizing the newly deposited extracellular matrix in bone. Retinoic acid and calcitriol influenced, respectively, proliferation and differentiation of osteoblasts, and an increase in PPARγ2 expression was observed following retinoic acid administration, whereas a decrease was observed following calcitriol administration. Aging widely influenced all parameters analyzed (the proliferation, differentiation, and new matrix deposition are significantly reduced in aged osteoblasts), with the exception of PPARγ2, which we found to be constitutively overexpressed and not modulated by retinoic acid or calcitriol administration. Our findings show the impaired ability of aged osteoblasts to perform adequate functional response and draw attention to the therapeutic approaches for bone healing in elderly patients.

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
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Termine JD (1990) Cellular activity, matrix proteins, and aging bone. Exp Gerontol 25:217–221

    Article  PubMed  CAS  Google Scholar 

  2. Bethel M, Chitetti BR, Srour E, Kacena MA (2013) The changing balance between osteoblastogenesis and adipogenesis in aging and its impact on hematopoiesis. Curr Osteoporos Rep 11:99–109

    Article  PubMed  PubMed Central  Google Scholar 

  3. Muruganandan S, Roman AA, Sinai CJ (2009) Adipocyte differentiation of bone-marrow derived mesenchymal stem cells: cross talk with the osteoblastogenic program. Cell Mol Life Sci 66:236–253

    Article  PubMed  CAS  Google Scholar 

  4. Lecka-Czernik B (2012) Marrow fat metabolism is linked to the systemic energy metabolism. Bone 50:534–539

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  5. Justesen J, Stenderup K, Ebbesen EN, Mosekilde L, Steiniche T, Kassem M (2001) Adipocytes tissue volume in bone marrow is increased with aging and in patients with osteoporosis. Biogerontology 2:165–171

    Article  PubMed  CAS  Google Scholar 

  6. Zhou S, Greenberger JS, Epperly MW, Goff JP, Adler C, Leboff MS, Glowacki J (2008) Age-related intrinsic changes in human bone-marrow derived mesenchymal stem cells and their differentiation to osteoblasts. Aging Cell 7:335–343

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  7. Moerman EJ, Teng KT, Lipschitz DA, Lecka-Czernik B (2004) Aging activates adipogenic and suppresses osteogenic programs in mesenchymal marrow stroma/stem cells: the role of PPARγ2 transcription factor and TGF-β/BMP signaling pathways. Aging Cell 3:379–389

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  8. Yamashita A, Takada T, Nemoto K, Yamamoto G, Torii R (2006) Transient suppression of PPARγ directed ES cells into an osteoblastic lineage. FEBS Lett 580:4121–4125

    Article  PubMed  CAS  Google Scholar 

  9. Lecka-Czernik B, Suva LJ (2006) Resolving the two “bony” faces of PPARγ. PPAR Res 2006:1–9

    Google Scholar 

  10. Cawthorn WP, Bree AJ, Yao Y, Du B, Hemati N, Martinez-Santibañez G, MacDougald OA (2012) Wnt6, Wnt10a and Wnt10b inhibit adipogenesis and stimulate osteoblastogenesis through a β-catenin-dependent mechanism. Bone 50:477–489

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  11. Rahman S, Czernik PJ, Lu Y, Lezcka-Czernik B (2012) β-Catenin directly sequesters adipocytic and insulin sensitizing activities but not osteoblastic activity of PPARγ2 in marrow stem cells. PLoS One 7:e51746

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  12. Bosetti M, Sabbatini M, Nicolì E, Fusaro L, Cannas M (2013) Effecs and differentiation activity of IGF-I and IGF-II, insulin and preptin on human primary bone cells. Growth Factors 31:57–65

    Article  PubMed  CAS  Google Scholar 

  13. Bennett CN, Ouyang H, Ma YL, Zeng Q, Gerin I, Sousa KM, Lane TF, Krishnan V, Hankenson KD, MacDougald OA (2007) Wnt10b increases postnatal bone formation by enhancing osteoblast differentiation. J Bone Miner Res 22:1924–1932

    Article  PubMed  CAS  Google Scholar 

  14. Anderson PH, Lam NN, Turner AG, Davey RA, Kogawa M, Atkins GJ, Morris HA (2013) The pleiotrophic effects of vitamin D in bone. J Steroid Biochem Mol Biol 136:190–194

    Article  PubMed  CAS  Google Scholar 

  15. Van Driel M, Koedam M, Buurman CJ, Roelse M, Weyts F, Chiba H, Uitterlinden AG, Pols HAP, van Leeuwen JPTM (2006) Evidence that both 1α,25-dhydroxyvitamin D3 and 24-hydroxylated D3 enhance human osteoblast differentiation and mineralization. J Cell Biochem 99:922–935

    Article  PubMed  Google Scholar 

  16. Ogston N, Harrison AJ, Cheung HF, Ashton BA, Hampson G (2002) Dexamethasone and retinoic acid differentially regulate growth and differentiation in an immortalised human clonal bone marrow stromal cell line with osteoblastic characteristics. Steroids 67:895–905

    Article  PubMed  CAS  Google Scholar 

  17. Skillington J, Choy L, Derynck R (2002) Bone morphogenetic protein and retinoic acid signaling cooperate to induce osteoblast differentiation of preadipocytes. J Cell Biol 159:135–146

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  18. Chambon P (1994) The retinoid signaling pathway: molecular and genetic analyses. Semin Cell Biol 5:115–125

    Article  PubMed  CAS  Google Scholar 

  19. Harada H, Miki R, Masushige S, Kato S (1995) Gene expression of retinoic acid receptors, retinoid-X receptors, and cellular retinol-binding protein I in bone and its regulation by vitamin A. Endocrinology 136:5329–5335

    PubMed  CAS  Google Scholar 

  20. Mangeldorf DJ, Thummel C, Beato M, Herrlich P, Schultz G, Umesono K, Blumberg B, Kastner P, Mark M, Evans R (1995) The nuclear receptor superfamily: the second decade. Cell 83:835–839

    Article  Google Scholar 

  21. Gimble JM, Zvonic S, Floyd ZE, Kassem M, Nutall ME (2006) Playing with bone and fat. J Cell Biochem 98:251–266

    Article  PubMed  CAS  Google Scholar 

  22. Maurin AC, Chavassieux PM, Meunier PJ (2005) Expression of PPARγ and β/δ in human primary osteoblastic cells: influence of polyunsaturated fatty acids. Calcif Tissue Int 76:385–392

    Article  PubMed  CAS  Google Scholar 

  23. Maurin AC, Chavassieux PM, Vericel E, Meunier PJ (2002) Role of polyunsaturated fatty acid in the inhibitory effect of human adipocytes on osteoblastic proliferation. Bone 31:260–266

    Article  PubMed  CAS  Google Scholar 

  24. Kerner J, Hoppel C (2000) Fatty acid import into mitochondria. Biochem Biophys Acta 1486:1–17

    PubMed  CAS  Google Scholar 

  25. Akimov SS, Krylov D, Fleischman LF, Belkin AM (2000) Tissue transglutaminase is an integrin-binding adhesion coreceptor for fibronectin. J Cell Biol 148:825–838

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  26. Heath DJ, Downes S, Verderio E, Griffin M (2001) Characterization of tissue transglutaminase in human osteoblast-like cells. J Bone Miner Res 16:1477–1485

    Article  PubMed  CAS  Google Scholar 

  27. Neve A, Corrado A, Cantatore FP (2013) Osteocalcin: skeletal and extra-skeletal effects. J Cell Physiol 228:1149–1153

    Article  PubMed  CAS  Google Scholar 

  28. Kaartinen MT, El-maadawy S, Rasanen NH, Mckee MD (2002) Tissue transglutaminase and its substrates in bone. J Bone Miner Res 17:2161–2173

    Article  PubMed  CAS  Google Scholar 

  29. Bosetti M, Vernè E, Ferraris M, Ravaglioli A, Cannas M (2001) In vitro characterization of zirconia coated by bioactive glass. Biomaterials 22:987–994

    Article  PubMed  CAS  Google Scholar 

  30. Karsten U, Wollenberger A (1977) Improvements in the ethidium bromide method for direct fluorimetric estimation of DNA and RNA in cell and tissue homogenates. Ann Biochem 77:464–470

    Article  CAS  Google Scholar 

  31. Hisada K, Hata K, Ichida F, Matsubara T, Orimo H, Nakano T, Yatani H, Nishimura R, Yoneda T (2013) Retinoic acid regulates commitment of undifferentiated mesenchymal stem cells into osteoblasts and adipocytes. J Bone Miner Metab 31:53–63

    Article  PubMed  CAS  Google Scholar 

  32. Ohishi K, Nishikawa S, Nagata T (1995) Phisiological concentrations of retinoic acid suppress the osteoblastic differentiation of fetal rat calvaria cells in vitro. Eur J Endocrinol 133:335–341

    Article  PubMed  CAS  Google Scholar 

  33. Rosen ED, Spiegelman BM (2001) PPARγ: a nuclear regulator of metabolism, differentiation, and cell growth. J Cell Biol Chem 276:37731–37734

    Article  CAS  Google Scholar 

  34. Khan E, Abu-Amer Y (2003) Ativation of peroxisome proliferator-activated receptor-γ inhibits differentiation of preosteoblasts. J Lab Clin Med 142:29–34

    Article  PubMed  CAS  Google Scholar 

  35. Han AJ, Tong C, Hu D, Bi XL, Yang WC (2008) A direct protein-protein interaction is involved in the suppression of β-catenin transcription by retinoid X receptor α in colorectal cancer cells. Cancer Biol Ther 7:454–459

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  36. Pacilli A, Calienni M, Margarucci S, D’Apolito M, Petillo O, Rocchi L, Pasquinelli G, Nicolai R, Koverech A, Calvani M, Peluso G, Montanaro L (2013) Carnitine-acyltransferase system inhibition, cancer cell death, and prevention of myc-induced lymphomagenesis. J Natl Cancer Inst 105:189–498

    Article  Google Scholar 

  37. Almeida M, Ambrogini E, Han L, Manolagas SC, Jilka RL (2009) Increased lipid oxidation causes oxidative stress, increate peroxisome proliferator-activated receptor-γ expression, and diminished pro-osteogenic Wnt signaling in the skeleton. J Biol Chem 284:27438–27448

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  38. Urano T, Shiraki M, Usui T, Sasaki N, Ouchi Y, Inoue S (2009) A1330 V variant of the low-density lipoprotein receptor-related protein 5 (LRP5) gene decreases Wnt signaling and affects the total body bone mineral density in Japanese women. Endocr J 56:625–631

    Article  PubMed  CAS  Google Scholar 

  39. Jiang Y, Mishima H, Sakai S, Liu Y-K, Ohyabu Y, Uemura T (2008) Gene expression analysis of major lineage-defining factors in human bone marrow cells: effect of aging, gender, and age-related disorders. J Orthoped Res 26:910–917

    Article  CAS  Google Scholar 

  40. Oudshoorn C, van der Cammen TJM, McMurdo MET, van Leeuwen JPTM, Colin EM (2009) Ageing and vitamin D deficiency: effects on calcium homeostasis and considerations for vitamin D supplementation. Br J Nutr 101:1597–1606

    Article  PubMed  CAS  Google Scholar 

  41. Yamaguchi M, Weitzmann MN (2012) High dose 1,25(OH)2D3 inhibits osteoblast mineralization in vitro. Int J Mol Med 29:934–938

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The research work was supported by University of Eastern Piedmont funds (ex 60 %) and MIUR funds (PRIN 2012 prot. 201288JKYY).

Conflict of interest

The authors declare they have no conflict of interest.

Author information

Authors and Affiliations

  1. Pharmacy Science Department, University of Eastern Piedmont, Alessandria, Novara, Vercelli, Italy

    Michela Bosetti

  2. Department of Health Sciences, University of Eastern Piedmont, Alessandria, Novara, Vercelli, Italy

    Maurizio Sabbatini, Alessia Borrone & Mario Cannas

  3. Institute of Protein Biochemistry, CNR, Naples, Italy

    Anna Calarco & Gianfranco Peluso

  4. Dipartmento Scienze della Salute, Università del Piemonte Orientale “Amedeo Avogadro”, via Solaroli 17, 28100, Novara, Italy

    Maurizio Sabbatini

Authors
  1. Michela Bosetti
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Maurizio Sabbatini
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Anna Calarco
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Alessia Borrone
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Gianfranco Peluso
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Mario Cannas
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Maurizio Sabbatini.

Additional information

M. Bosetti and M. Sabbatini contributed equally to this work.

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bosetti, M., Sabbatini, M., Calarco, A. et al. Effect of retinoic acid and vitamin D3 on osteoblast differentiation and activity in aging. J Bone Miner Metab 34, 65–78 (2016). https://doi.org/10.1007/s00774-014-0642-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00774-014-0642-2

Keywords

Search

Navigation