Molecular interactions of FGF23 and PTH in phosphate regulation

Bone-derived fibroblast growth factor-23 (FGF23) plays an important role in systemic phosphate turnover. Increased FGF23 activity results in hypophosphatemic, while reduced activity is linked to hyperphosphatemic disorders. FGF23, together with klotho as co-factor, can activate FGF-receptors in its target tissues to exert its functions. However, molecular regulation of FGF23 synthesis is not clearly defined, and recent studies have found that PTH can activate the nuclear receptor-associated protein-1 (Nurr1) to induce FGF23 transcription in bone cells

Endocrine Regulation of Phosphate Homeostasis

author's chapter in edited workPhosphate, a component of nucleic acids, DNA and RNA, is incorporated in the structure of phospholipids in cell membranes, and is involved in many biological functions such as cell signaling, energy metabolism, and bone mineralization. Phosphate homeostasis is regulated by intestinal phosphate absorption, renal phosphate reabsorption, and skeletal phosphate resorption. Renal and intestinal transport of inorganic phosphate is controlled by sodium-phosphate cotransporters. Endocrine regulators that target bone, kidneys, and intestines during phosphate homeostasis include parathyroid hormone, vitamin D, fibroblast growth factor 23 (FGF23), and Klotho. Dysregulated serum phosphate falls within two categories: hypophosphatemia and hyperphosphatemia. Some genetic disorders such as hypophosphatemic rickets overexpress FGF23, inhibiting renal reabsorption of inorganic phosphate, while other disorders such as familial tumor calcinosis inhibit the expression of FGF23, causing hyperphosphatemia. Conditions associated with phosphate toxicity include chronic kidney disease, vascular calcification, tumorigenesis, and premature aging

Dysregulation of Phosphate Metabolism and Conditions Associated With Phosphate Toxicity

Phosphate homeostasis is coordinated and regulated by complex cross-organ talk through delicate hormonal networks. Parathyroid hormone (PTH), secreted in response to low serum calcium, has an important role in maintaining phosphate homeostasis by influencing renal synthesis of 1,25-dihydroxyvitamin D, thereby increasing intestinal phosphate absorption. Moreover, PTH can increase phosphate efflux from bone and contribute to renal phosphate homeostasis through phosphaturic effects. In addition, PTH can induce skeletal synthesis of another potent phosphaturic hormone, fibroblast growth factor 23 (FGF23), which is able to inhibit renal tubular phosphate reabsorption, thereby increasing urinary phosphate excretion. FGF23 can also fine-tune vitamin D homeostasis by suppressing renal expression of 1-alpha hydroxylase (1α(OH)ase). This review briefly discusses how FGF23, by forming a bone-kidney axis, regulates phosphate homeostasis, and how its dysregulation can lead to phosphate toxicity that induces widespread tissue injury. We also provide evidence to explain how phosphate toxicity related to dietary phosphorus overload may facilitate incidence of noncommunicable diseases including kidney disease, cardiovascular disease, cancers and skeletal disorders

Phosphate toxicity and tumorigenesis

The final publication is available at Elsevier via http://dx.doi.org/10.1016/j.bbcan.2018.04.007 © 2018. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/In this article, we briefly summarized evidence that cellular phosphate burden from phosphate toxicity is a pathophysiological determinant of cancer cell growth. Tumor cells express more phosphate cotransporters and store more inorganic phosphate than normal cells, and dysregulated phosphate homeostasis is associated with the genesis of various human tumors. High dietary phosphate consumption causes the growth of lung and skin tumors in experimental animal models. Additional studies show that excessive phosphate burden induces growth-promoting cell signaling, stimulates neovascularization, and is associated with chromosome instability and metastasis. Studies have also shown phosphate is a mitogenic factor that affects various tumor cell growth. Among epidemiological evidence linking phosphate and tumor formation, the Health Professionals Follow-Up Study found that high dietary phosphate levels were independently associated with lethal and high-grade prostate cancer. Further research is needed to determine how excessive dietary phosphate consumption influences initiation and promotion of tumorigenesis, and to elucidate prognostic benefits of reducing phosphate burden to decrease tumor cell growth and delay metastatic progression. The results of such studies could provide the basis for therapeutic modulation of phosphate metabolism for improved patient outcome

Heat Shock Protein 47: A Novel Biomarker of Phenotypically Altered Collagen-Producing Cells

Heat shock protein 47 (HSP47) is a collagen-specific molecular chaperone that helps the molecular maturation of various types of collagens. A close association between increased expression of HSP47 and the excessive accumulation of collagens is found in various human and experimental fibrotic diseases. Increased levels of HSP47 in fibrotic diseases are thought to assist in the increased assembly of procollagen, and thereby contribute to the excessive deposition of collagens in fibrotic areas. Currently, there is not a good universal histological marker to identify collagen-producing cells. Identifying phenotypically altered collagen-producing cells is essential for the development of cell-based therapies to reduce the progression of fibrotic diseases. Since HSP47 has a single substrate, which is collagen, the HSP47 cellular expression provides a novel universal biomarker to identify phenotypically altered collagen-producing cells during wound healing and fibrosis. In this brief article, we explained why HSP47 could be used as a universal marker for identifying phenotypically altered collagen-producing cells

Vitamin D supplements: Magic pill or overkill?

Vitamin D is a multifunctional micronutrient that exerts hormonal effects on many organs of the body. 1,25 dihydroxyvitamin D is the active metabolite of vitamin D, formed by dual hydroxylation in the liver and kidney