Calcium phosphate-bearing matrices induce osteogenic differentiation of stem cells through adenosine signaling

Yu Ru V. Shih, Yongsung Hwang, Ameya Phadke, Heemin Kang, Nathaniel S. Hwang, Eduardo J. Caro, Steven Nguyen, Michael Siu, Emmanuel A. Theodorakis, Nathan C. Gianneschi, Kenneth S. Vecchio, Shu Chien, Oscar K. Lee, Shyni Varghese

Research output: Contribution to journalArticlepeer-review

290 Citations (Scopus)


Synthetic matrices emulating the physicochemical properties of tissue-specific ECMs are being developed at a rapid pace to regulate stem cell fate. Biomaterials containing calcium phosphate (CaP) moieties have been shown to support osteogenic differentiation of stem and progenitor cells and bone tissue formation. By using a mineralized synthetic matrix mimicking a CaP-rich bone microenvironment, we examine a molecular mechanism through which CaP minerals induce osteogenesis of human mesenchymal stem cells with an emphasis on phosphate metabolism. Our studies show that extracellular phosphate uptake through solute carrier family 20 (phosphate transporter), member 1 (SLC20a1) supports osteogenic differentiation of human mesenchymal stem cells via adenosine, an ATP metabolite, which acts as an autocrine/paracrine signaling molecule through A2b adenosine receptor. Perturbation of SLC20a1 abrogates osteogenic differentiation by decreasing intramitochondrial phosphate and ATP synthesis. Collectively, this study offers the demonstration of a previously unknown mechanism for the beneficial role of CaP biomaterials in bone repair and the role of phosphate ions in bone physiology and regeneration. These findings also begin to shed light on the role of ATP metabolism in bone homeostasis, which may be exploited to treat bone metabolic diseases.

Original languageEnglish
Pages (from-to)990-995
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number3
Publication statusPublished - 2014 Jan 21
Externally publishedYes


  • Biomimetic material
  • Bone metabolism
  • Mineralized matrix
  • Phosphate signaling

ASJC Scopus subject areas

  • General


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