Skeletal FGF23 production mediated by GPCR/Gq/PKC signaling

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Abstract Fibroblast growth factor-23 (FGF23), a bone-derived phosphaturic hormone, plays a key role in the regulation of serum phosphate levels and vitamin D metabolism. Dysregulated FGF23 actions underlie the pathogenesis of several skeletal diseases with abnormal mineral ion metabolism. Serum FGF23 levels also rise in kidney failure, and elevated FGF23 levels contribute greatly to the mineral and bone disorder associated with chronic kidney disease. Effective strategies for controlling skeletal FGF23 production are needed in order to improve the clinical management of these disorders. However, mechanisms governing FGF23 production remain poorly defined, impeding progress toward this goal. Several FGF23 stimulators have been described, but the molecular determinants of their actions are incompletely understood. The intracellular signaling pathways are not elucidated, and it remains unknown how those interact with one another. We have now identified lysophosphatidic acid (LPA) as a novel stimulator of FGF23 synthesis and found that it acts through its G protein-coupled receptor LPAR1. We also showed that ablation of LPAR1 blocks the rise of FGF23 in a mouse model of acute kidney injury. Our preliminary experiments also strongly suggested that the action of LPA involves Gq/11/PKC signaling pathway operating via a mechanism that depends on MAPK-ERK1/2 signaling. Moreover, our results strongly suggested that the LPA-Gq/11/PKC pathway is critical for FGF23 production induced by 1,25-dihydroxyvitamin D (1,25D). In this proposal, we will investigate this novel paradigm of FGF23 synthesis in osteocytes. Aim 1 will determine the role of osteocyte-specific Gq/11/PKC signaling in LPA-induced FGF23 production, examine the interaction of this pathway with MAPK-ERK1/2 signaling, and determine whether it plays a role in the dietary phosphate-induced elevation of FGF23 levels. For those studies, we will employ mice in which Gq/11α are ablated conditionally in osteocytes (Gq/11αDmp1KO mice, available in our lab), as well as osteocyte/osteoblast-like cell lines suitable for studying FGF23 synthesis. Aim 2 will elucidate the cross-talk between the action of 1,25D and LPA-Gq/11/PKC signaling in FGF23 production, using both cell- based assays and mouse models (Gq/11αDmp1KO and vitamin D receptor knockout mice, also available in our lab). Aim 3 will examine the role of Gq/11/PKC signaling in pathological conditions of excess FGF23 production, including X-linked hypophosphatemic rickets (XLH) and renal failure. We will employ Hyp mice (an established model of XLH), which will be crossed with Gq/11αDmp1KO mice. For studying renal failure-induced FGF23 overproduction, we will use a model of chronic kidney disease induced by adenine-rich diet. Our studies will elucidate the role of the LPA-Gq/11/PKC pathway as a stimulator of FGF23 production in osteocytes and identify its relationship with the cellular actions of other important systemic regulators of FGF23 synthesis. Our predicted results will thus markedly increase the knowledge of the mechanisms controlling FGF23 synthesis and are likely to yield new drug targets for diseases caused or affected by dysregulated FGF23 actions.