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bioRxiv · 10.64898/2025.12.01.691659

TGF-β signaling regulates the response of the skeleton to phosphate

Zhu, E. K.·Kuennen, D. P.·Tran, L.·Kostalidis, P. E.·Mannstadt, M.·Surface, L. E.
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Abstract

Inorganic phosphate (Pi) homeostasis is crucial to organismal health, yet the mechanisms underlying the regulation of it remain unclear. Critically, we lack a clear understanding of the Pi response circuitry in osteogenic cells that identifies altered serum Pi levels and transmits this information to changes in serum FGF23 levels, a key hormone regulating circulating Pi. We utilized genome-wide CRISPR screens in osteogenic Pi-responsive fluorescent reporter cell lines to identify regulators of the response to high phosphate, intersecting those results with loci associated with circulating FGF23 levels by genome-wide association studies (GWAS) and identified a potential role for TGF-{beta}2. We found that each of the three ligands (TGF-{beta}1, 2, 3) can enhance the response to Pi in osteogenic cell lines and ex vivo cultures of calvariae, while inhibitors of TGF{beta} receptor signaling dampen it. Co-treatment of Pi with TGF{beta} ligands led to an elevated, synergistic transcriptional induction of Slc20a1, which encodes a key Pi importer, which corresponded with an increased intracellular uptake of phosphate. Furthermore, in mice, blocking TGF{beta} signaling disrupted the induction of FGF23 in mice on a high phosphate diet, resulting in disrupted downstream endocrine control of phosphate homeostasis. Together, these findings reveal a role for TGF{beta} signaling in the regulation of phosphate homeostasis in osteogenic cells through regulation of cellular phosphate uptake, which in turn contributes to the maintenance of organismal phosphate homeostasis.

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Zhu, E. K., Kuennen, D. P., Tran, L., Kostalidis, P. E., Mannstadt, M., Surface, L. E.. 2025-12-03. TGF-β signaling regulates the response of the skeleton to phosphate. https://doi.org/10.64898/2025.12.01.691659

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