Role of phosphate sensing in bone and mineral metabolism

Abstract

Inorganic phosphate (P) is essential for signal transduction and cell metabolism, and is also an essential structural component of the extracellular matrix of the skeleton. P is sensed in bacteria and yeast at the plasma membrane, which activates intracellular signal transduction to control the expression of P transporters and other genes that control intracellular P levels. In multicellular organisms, P homeostasis must be maintained in the organism and at the cellular level, requiring an endocrine and metabolic P-sensing mechanism, about which little is currently known. This Review will discuss the metabolic effects of P, which are mediated by P transporters, inositol pyrophosphates and SYG1-Pho81-XPR1 (SPX)-domain proteins to maintain cellular phosphate homeostasis in the musculoskeletal system. In addition, we will discuss how P is sensed by the human body to regulate the production of fibroblast growth factor 23 (FGF23), parathyroid hormone and calcitriol to maintain serum levels of P in a narrow range. New findings on the crosstalk between iron and P homeostasis in the regulation of FGF23 expression will also be outlined. Mutations in components of these metabolic and endocrine phosphate sensors result in genetic disorders of phosphate homeostasis, cardiomyopathy and familial basal ganglial calcifications, highlighting the importance of this newly emerging area of research.

Importance of Dietary Phosphorus for Bone Metabolism and Healthy Aging

“…In turn, P i feeds back to regulate the secretion of these hormones. This process is often referred to as endocrine P i sensing [ 46 ] but is still poorly understood (for several excellent reviews, see [ 46 , 47 , 48 ]).…”

“…PTH is a peptide of 84 amino acids that is secreted by the parathyroid glands and signals through the PTH and PTH-related protein receptor [(also known as parathyroid hormone receptor 1 (PTHR1)], which is expressed in osteoblasts, osteocytes, chondrocytes, and proximal tubular cells [ 46 ]. P i stimulates the secretion of PTH in the parathyroids, which in turn stimulates the synthesis of calcitriol in the proximal tubules and thereby indirectly stimulates intestinal P i absorption [ 66 ].…”

Identity and functions of inorganic and inositol polyphosphates in plants

“…Mutation of the PP-InsP-binding lysine cluster on the SPX domain of PHO1, the prototypical Arabidopsis SPX-EXS, abrogates its ability to transport Pi from roots to shoots, causing a dramatic decrease in shoot Pi content (Wild et al, 2016). Similarly, mutations on the SPX domain of XPR1, a PHO1 homolog and the sole human SPXcontaining protein, are responsible for primary familial brain calcification disorders that are most likely caused by Pi transport deficiencies (Chande & Bergwitz, 2018). The mechanism by which PP-InsP binding to the SPX domain activates these transporters has not yet been established.…”

Slc20a1/Pit1 and Slc20a2/Pit2 are essential for normal skeletal myofiber function and survival

“…In addition to its function as a substrate for ATP production, Pi activates ERK1/2 in myocytes like in many other cells 22 (Fig. 7).…”

“…Likewise, mice with global ablation of Slc20a2/Pit2 are fertile, appear to thrive normally and have comparable body weights without reported skeletal muscle phenotypes [16][17][18][19] . Interestingly, recent evidence suggests that Pit1 can stimulate cell proliferation 20 , gene expression 11 , apoptosis 21 and activation of the mitogen-activated kinases ERK1/2 in many cells including myocytes 11,22 independently of its transport activity. MAPK phosphatases (MKPs) can both positively and negatively regulate myogenesis through coordinate MAPK dephosphorylation [23][24][25][26] .…”