FGF23 is a putative marker for bone healing and regeneration

Abstract

Besides numerous other factors, fibroblast growth factor receptor (FGFR) signaling is involved in fracture healing and bone remodeling. FGF23 is a phosphatonin produced by osteoblastic cells, which signals via FGFR1, thereby exerting effects in bone and kidney. We analyzed if serum FGF23 levels might be an indicator to predict fracture healing and union. FGF23 (C-Term) was elevated on day 3 postoperatively in 55 patients sustaining an exchange of total hip implants due to aseptic loosening. A prospective study of 40 patients undergoing primary hip arthroplasty also showed elevated FGF23 (C-Term) but no change in FGF23 (intact) levels on days 1, 4, and 10 postoperatively. Serum phosphate and phosphate clearance stayed within normal ranges. FGF23 mRNA expression in ovine callus was compared between a standard and delayed course of osteotomy healing. In the standard model, a marked increase in FGF23 mRNA expression compared to the delayed healing situation was observed. Immunohistochemical analysis showed FGF23 production of osteoblasts and granulation tissue in the fracture callus during bone healing. In conclusion, FGF23 is involved in bone healing, can be measured by a sensitive assay in peripheral blood, and is a promising candidate as an indicator for healing processes prone to reunion versus nonunion. Keywords: fibroblast growth factor 23; fracture healing; phosphate; arthroplasty Fibroblast growth factor 23 (FGF23) is a FGF family member that is expressed mainly in osteocytes. In pathophysiological conditions such as fibrous dysplasia osteoblasts and preosteoblasts are reported to produce FGF23. 1 The expression of FGF23 in chondrocytes, osteoclasts, and pericytes has also been shown.2 FGF23 signals are mediated via the FGF receptor 1(IIIc): the combined binding of FGF23 and the antiageing hormone Klotho has been shown to convert FGFR1 to an FGF23-specific receptor.3-7 FGF23 was originally identified and cloned as a causative factor for tumor induced osteomalacia (TIO), where mostly benign tumors overexpress phosphaturic factors such as FGF23, which causes renal phosphate wasting. [8][9][10] High FGF23 concentrations are associated with impaired 1a-hydroxylase activity in the kidney, leading to low 1,25(OH)2 vitamin D3 levels. [11][12][13] Additionally, the expression of the renal sodium phosphate transporters Npt1, Npt2a, and NPT2c is down-regulated by FGF23, thereby influencing the systemic regulation of phosphate metabolism.14,15 The FGF23 gene is linked to several inheritable syndromes such as autosomal dominant hypophosphatemic rickets (ADHR, gain of function mutations) and tumoral calcinosis (TC, loss of function mutations). ADHR results from a lack in protein processing by subtilisin-like-proteases due to a mutated RXXR cleavage motif within the protein structure. [16][17][18] TC is caused by either a mutation in GALNT3, a glycosyltransferase responsible for FGF23 glycosylation, or a mutation in a highly conserved FGF23 region resulting in decreased secretion. [19][20][21] Besides its functi...

<b>Immunolocalization of osteocyte-derived molecules during bone fracture healing of mouse </b><b>ribs </b>

“…Chondrogenesis and subsequent chondrocytic proliferation and differentiation are regulated by Wnt/ FGF23; instead, fibroblastic cells in the bone marrow became FGF23-positive as early as post-fracture day 4, remaining so throughout post-fracture week 3. Goebel et al have reported that FGF23 was synthesized in the granulation tissues surrounding bone fracture sites, suggesting that FGF23 is a possible parameter for bone healing (12). In our study, FGF23-producing fibroblastic cells were seen early in the bone marrow, and were still present in the granulation tissue 3 weeks after the fracture.…”

Klotho/FGF23 Axis in Chronic Kidney Disease and Cardiovascular Disease

“…FGF23 Cterminal enzyme-linked immunosorbent assay (ELISA) yields the sum of the C-terminal fragment and intact FGF23 [74,75] , whereas FGF23 intact ELISA simply yields iFGF23, which constitutes the biological activity of FGF23 and is involved in pathophysiological processes in subjects with CKD and other phosphatemic disorders [74,76,77] . Animal studies have shown that an increase in cFGF23 by C-terminal ELISA may be due to the increase in C-terminal fragments acting as an acute-phase reactant under stressful conditions because iFGF23 was not elevated [78] . This concept in CKD patients is still uncertain and needs to be confirmed.…”

FGF23/Klotho New Regulators of Vitamin D Metabolism

“…Recent studies indicate that FGF23 is increased in callus during fracture healing, consistent with local matrixderived FGF23-stimulating factors [110]. It is also possible that the discrepancies between PTH lack of a direct effect on FGF23 promoter activity and the 42.…”