Augmented Fibroblast Growth Factor-23 Secretion in Bone Locally Contributes to Impaired Bone Mineralization in Chronic Kidney Disease in Mice

Abstract

Chronic kidney disease-mineral and bone disorder (CKD-MBD) is a systemic disorder of mineral and bone metabolism caused by CKD. Impaired bone mineralization together with increased bony secretion of fibroblast growth factor-23 (FGF23) are hallmarks of CKD-MBD. We recently showed that FGF23 suppresses the expression of tissue nonspecific alkaline phosphatase (TNAP) in bone cells by a Klotho-independent, FGF receptor-3-mediated signaling axis, leading to the accumulation of the mineralization inhibitor pyrophosphate. Therefore, we hypothesized that excessive FGF23 secretion may locally impair bone mineralization in CKD-MBD. To test this hypothesis, we induced CKD by 5/6 nephrectomy in 3-month-old wild-type (WT) mice and Fgf23−/−/VDRΔ/Δ (Fgf23/VDR) compound mutant mice maintained on a diet enriched with calcium, phosphate, and lactose. Eight weeks postsurgery, WT CKD mice were characterized by reduced bone mineral density at the axial and appendicular skeleton, hyperphosphatemia, secondary hyperparathyroidism, increased serum intact Fgf23, and impaired bone mineralization as evidenced by bone histomorphometry. Laser capture microdissection in bone cryosections showed that both osteoblasts and osteocytes contributed to the CKD-induced increase in Fgf23 mRNA abundance. In line with our hypothesis, osteoblastic and osteocytic activity of alkaline phosphatase was reduced, and bone pyrophosphate concentration was ~2.5-fold higher in CKD mice, relative to Sham controls. In Fgf23/VDR compound mice lacking Fgf23, 5/6-Nx induced secondary hyperparathyroidism and bone loss. However, 5/6-Nx failed to suppress TNAP activity, and bone pyrophosphate concentrations remained unchanged in Fgf23/VDR CKD mice. Collectively, our data suggest that elevated Fgf23 production in bone contributes to the mineralization defect in CKD-MBD by auto-/paracrine suppression of TNAP and subsequent accumulation of pyrophosphate in bone. Hence, our study has identified a novel mechanism involved in the pathogenesis of CKD-MBD.

The EPO-FGF23 Signaling Pathway in Erythroid Progenitor Cells: Opening a New Area of Research

“…Osteopontin secretion is indirectly downregulated by FGF23 signaling: lower availability of extracellular phosphate suppresses osteopontin expression (Murali et al, 2016b). Although, acting locally, also high systemically circulating FGF23 could modulate pyrophosphate metabolism (Murali et al, 2016a,b; Andrukhova et al, 2018). Moreover, alterations in vitamin D metabolism contribute to impaired bone mineralization in response to iFGF23.…”

“…So, iFGF23 signaling results directly in impaired bone mineralization via TNAP suppression. Notably, current knowledge is based on FGF23-knockout models, thereby not reflecting the interplay of iFGF23 and cFGF23 (Murali et al, 2016a,b; Andrukhova et al, 2018).…”

Increased FGF-23 levels are linked to ineffective erythropoiesis and impaired bone mineralization in myelodysplastic syndromes

“…Finally, in CKD, Fgf23 mRNA transcription is increased in bone cells early in the disease course, likely due to inflammatory signals and iron deficiency, which are both inducers of FGF-23. This leads to normal or high serum phosphate and a high iFGF-23/cFGF-23 ratio (24,42,45,51,53). However, with increasing impairment of kidney function, renal phosphate excretion is reduced, leading to a progressive increase in serum phosphate.…”

Phenomenon of osteocyte lacunar mineralization: indicator of former osteocyte death and a novel marker of impaired bone quality?

“…For this goal, osteocytes produce crystallization and mineralization inhibitors (SIBLING proteins such as osteopontin and MEPE, fetuin-A or tethering elements' component -perlecan) as well as enzymes for active digestion of their direct surroundings (such as matrix metalloproteinases) (96,99,100,101) to prevent spontaneous calcium and phosphorus precipitation around the cell (102,103) and are even able to dissolve bone minerals, as observed in lactation (10). Additional molecules involved in the process may be locally produced FGF23 and osteopontin, as animal studies suggested that increased local production of FGF23 by osteocytes reduces activity of alkaline phosphatase, leading to increased levels of pyrophosphate, a known mineralization inhibitor (104). However, following osteocyte death, the lack of crystallization inhibitors allows spontaneous mineralization of the lacuna and canaliculi, given the normally available calcium in the extracellular space.…”