Abstract
The discovery that osteocytes secrete phosphaturic fibroblast growth factor 23 (FGF23) has defined bone as an endocrine organ. However, the autocrine and paracrine functions of FGF23 are still unknown. The present study focuses on the cellular and molecular mechanisms involved in the complex control of FGF23 production and local bone remodeling functions. FGF23 was assayed using ELISA kit in the presence or absence of 17β–estradiol in starved MLO-Y4 osteocytes. In these cells, a relationship between oxidative stress-induced apoptosis and up-regulation of active FGF23 levels due to MAP Kinases activation with involvement of the transcriptional factor (NF-kB) has been demonstrated. The active FGF23 increase can be due to up-regulation of its expression and post-transcriptional modifications. 17β–estradiol prevents the increase of FGF23 by inhibiting JNK and NF-kB activation, osteocyte apoptosis and by the down-regulation of osteoclastogenic factors, such as sclerostin. No alteration in the levels of dentin matrix protein 1, a FGF23 negative regulator, has been determined. The results of this study identify biological targets on which drugs and estrogen may act to control active FGF23 levels in oxidative stress-related bone and non-bone inflammatory diseases.
Highlights
Fibroblast growth factor 23 (FGF23), a phosphaturic hormone produced primarily by osteocytes and osteoblasts [1,2,3], plays an important role in the regulation of phosphate (Pi) homeostasis and bone mineralization [4]
Osteocytes are the primary source of FGF23 and other factors related to its action and regulation, such as phosphate regulating endopeptidase homolog X-linked (PHEX), dentin matrix protein 1 (DMP1), matrix extracellular phosphoglycoprotein (MEPE), and sclerostin [11,12]
The novel data in the present study show a relationship between oxidative stress-induced apoptosis (OSIA) and the upregulation of the intra- and extracellular levels of active FGF23 due to activation of both Jun N-terminal kinase (JNK) and ERK1/2 signaling pathways, with the involvement of NF-κB, in starved MLO-Y4 cells. 17β–E2 inhibits quickly and in the presence of oxidative stress the osteocyte apoptosis and activation of osteoclastogenic factors [43], with consequent active FGF23 decrease
Summary
Fibroblast growth factor 23 (FGF23), a phosphaturic hormone produced primarily by osteocytes and osteoblasts [1,2,3], plays an important role in the regulation of phosphate (Pi) homeostasis and bone mineralization [4]. FGF23 down-regulates the expression of the sodium phosphate cotransporter, stimulating the release of Pi in the urine, and preventing the 1α-hydroxylation of 25-hydroxyvitamin D (25-(OH)D) with consequent decrease in the absorption of calcium and Pi by the intestine [6] These changes cause decrease of blood Pi and 1-25-(OH)D levels, and the activation of FGF23 secretion both in vivo and in vitro [7,8]. The intact circulating form of FGF23 (32–35 KDa) is the biologically active molecule (active FGF23) which undergoes mucin-type O-glycosylation in the Golgi apparatus of osteocytes by the enzyme N-acetyl galactosaminyltransferase 3 (GalNT3) This is required for the secretion of active FGF23 by blocking its proteolytic cleavage by the protease furin. An increase of active FGF23 is related to hypophosphatemic pathologies such as X-linked hypophosphatemic rickets and tumor-induced osteomalacia [19]
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