Low extracellular sodium promotes adipogenic commitment of human mesenchymal stromal cells: a novel mechanism for chronic hyponatremia-induced bone loss
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Hyponatremia represents an independent risk factor for osteoporosis and fractures, affecting both bone density and quality. A direct stimulation of bone resorption in the presence of reduced extracellular sodium concentrations ([Na+]) has been shown, but the effects of low [Na+] on osteoblasts have not been elucidated. We investigated the effects of a chronic reduction of extracellular [Na+], independently of osmotic stress, on human mesenchymal stromal cells (hMSC) from bone marrow, the common progenitor for osteoblasts and adipocytes. hMSC adhesion and viability were significantly inhibited by reduced [Na+], but their surface antigen profile and immuno-modulatory properties were not altered. In low [Na+], hMSC were able to commit toward both the osteogenic and the adipogenic phenotypes, as demonstrated by differentiation markers analysis. However, the dose-dependent increase in the number of adipocytes as a function of reduced [Na+] suggested a preferential commitment toward the adipogenic phenotype at the expense of osteogenesis. The amplified inhibitory effect on the expression of osteoblastic markers exerted by adipocytes-derived conditioned media in low [Na+] further supported this observation. The analysis of cytoskeleton showed that low [Na+] were associated with disruption of tubulin organization in hMSC-derived osteoblasts, thus suggesting a negative effect on bone quality. Finally, hMSC-derived osteoblasts increased their expression of factors stimulating osteoclast recruitment and activity. These findings confirm that hyponatremia should be carefully taken into account because of its negative effects on bone, in addition to the known neurological effects, and indicate for the first time that impaired osteogenesis may be involved.
KeywordsOsteoporosis Chronic hyponatremia Mesenchymal stromal cells Bone marrow adipogenetic/osteogenetic balance
The authors wish to thank Ente Cassa di Risparmio di Firenze for supporting the study.
Conflict of interest
Benedetta Fibbi, Susanna Benvenuti, Corinna Giuliani, Cristiana Deledda, Paola Luciani, Monica Monici, Benedetta Mazzanti, Clara Ballerini, and Alessandro Peri declare that they have no conflict of interest.
- 7.R. Hasserius, M.K. Karlsson, B.E. Nilsson, I. Redlund-Johnell, O. Johnell, Prevalent vertebral deformities predict increased mortality and increased fracture rate in both men and women: a 10-year population-based study of 598 individuals from the Swedish cohort in the European Vertebral Osteoporosis Study. Osteoporosis Int. 14, 61–68 (2003)CrossRefGoogle Scholar
- 24.R. Tamma, L. Sun, C. Cuscito, P. Lu, M. Corcelli, J. Li, G. Colaianni, S.S. Moonga, A. Di Benedetto, M. Grano, S. Colucci, T. Yuen, M.I. New, A. Zallone, M. Zaidi, Regulation of bone remodeling by vasopressin explains the bone loss in hyponatremia. Proc. Natl. Acad. Sci. USA 110, 18644–18649 (2013)CrossRefPubMedPubMedCentralGoogle Scholar
- 26.E.J. Moerman, K. Teng, D.A. Lipschitz, B. Lecka-Czernik, Aging activates adipogenic and suppresses osteogenic programs in mesenchymal marrow stroma/stem cells: the role of PPARγ2 transcription factor and TGF-β/BMP signalling pathways. Aging Cell 3, 379–389 (2004)CrossRefPubMedPubMedCentralGoogle Scholar
- 29.S. Benvenuti, I. Cellai, P. Luciani, C. Deledda, S. Baglioni, C. Giuliani, R. Saccaridi, B. Mozzanti, S. Dal Pozzo, E. Mannucci, A. Peri, M. Serio, Rosiglitazone stimulates adipogenesis and decreases osteoblastogenesis in human mesenchymal stem cells. J. Endocrinol. Invest. 30, RC26–RC30 (2007)CrossRefPubMedGoogle Scholar
- 37.M. Zhao, S. Ko, J.H. Liu, D. Chen, J. Zhang, B. Wang, S.E. Harris, B.O. Oyajobi, G.R. Mundy, Inhibition of microtubule assembly in osteoblasts stimulates bone morphogenetic protein 2 expression and bone formation through transcription factor Gli2. Mol. Cell. Biol. 29, 1291–1305 (2009)CrossRefPubMedPubMedCentralGoogle Scholar
- 38.H.F. Al-Jallad, V.D. Myneni, S.A. Piercy-Kotb, N. Chabot, A. Mulani, J.W. Keillor, M.T. Kaartinen, Plasma membrane factor XIIIA transglutaminase activity regulates osteoblast matrix secretion and deposition by affecting microtubule dynamics. PLoS One 6, e15893 (2011)CrossRefPubMedPubMedCentralGoogle Scholar
- 40.A.P. Molloy, F.T. Martin, R.M. Dwyer, T.P. Griffin, M. Murphy, F.P. Barry, T. O’Brien, M.J. Kerin, Mesenchymal stem cell secretion of chemokines during differentiation into osteoblasts, and their potential role in mediating interactions with breast cancer cells. Int. J. Cancer 124, 326–332 (2009)CrossRefPubMedGoogle Scholar