Endogenous FGF‐2 is critically important in PTH anabolic effects on bone

Abstract

Parathyroid hormone (PTH) increases Fibroblast growth factor receptor-1 (FGFR1) and Fibroblast growth factor-2 (FGF-2) expression in osteoblasts and the anabolic response to PTH is reduced in Fgf2−/− mice. This study examined whether candidate factors implicated in the anabolic response to PTH were modulated in Fgf2−/− osteoblasts. PTH increased Runx-2 protein expression in Fgf2+/+ but not Fgf2−/− osteoblasts. By immunocytochemistry, PTH treatment induced nuclear accumulation of Runx-2 only in Fgf2+/+ osteoblasts. PTH and FGF-2 regulate Runx-2 via activation of the cAMP response element binding proteins (CREBs). Western blot time course studies showed that PTH increased phospho-CREB within 15 min that was sustained for 24 h in Fgf2+/+ but had no effect in Fgf2−/− osteoblasts. Silencing of FGF-2 in Fgf2+/+ osteoblasts blocked the stimulatory effect of PTH on Runx-2 and CREBs phosphorylation. Studies of the effects of PTH on proteins involved in osteoblast precursor proliferation and apoptosis showed that PTH increased cyclinD1-cdk4/6 protein in Fgf2+/+ but not Fgf2−/− osteoblasts. Interestingly, PTH increased the cell cycle inhibitor p21/waf1 in Fgf2−/− osteoblasts. PTH increased Bcl-2/Bax protein ratio in Fgf2+/+ but not Fgf2−/− osteoblasts. In addition PTH increased cell viability in Fgf2+/+ but not Fgf2−/− osteoblasts. These data suggest that endogenous FGF-2 is important in PTH effects on osteoblast proliferation, differentiation and apoptosis. Reduced expression of these factors may contribute to the reduced anabolic response to PTH in the Fgf2−/− mice. Our results strongly indicate that the anabolic PTH effect is dependent in part on FGF-2 expression.

The dual face of parathyroid hormone and prostaglandins in the osteoimmune system

“…The current findings concur that osteoblasts are recruited in distinct areas called "basic multicellular units" by osteoclasts via cross-talk between both cell types and begin to lay down new bone matrixes (14,25). This complex and dynamic equilibrium of bone cells is regulated by several systemic factors, such as bone morphogenetic proteins (68,97,102,146), parathyroid hormone (PTH) (39,73,100), and prostaglandins (PGs) (3,4,99,101), as well as shared cytokines, transcription factors, and membrane receptors in the immune and skeletal systems (49,123). Modern research has argued that these two systems interact with each other and that impaired cross-talk between the distinct niches in the marrow creates pathological conditions like chronic inflammatory joint diseases, known as rheumatoid arthritis (RA) (27,38) and chronic arthritis (16), which lead to decreased bone density and alter the mechanical properties of the bone itself.…”

“…Likewise, we have shown that PTH treatment in vitro increases osteoblast survival and differentiation base on time and dose. Fibroblast growth factor-2 (FGF-2) plays a part in these effects (100). In point of fact, intermittent PTH administration is an approved treatment modality for osteoporosis (18,73 2 (Ostabolin-C) show promising effects against osteoporosis by strongly stimulating bone formation and strengthening bone microarchitecture in humans, monkeys, and rodents with few or no side effects (141,142).…”

BMP-2 Differentially Modulates FGF-2 Isoform Effects in Osteoblasts From Newborn Transgenic Mice

“…We have also shown that overexpression of the HMW/nuclear isoforms preferentially mediate augmented osteoblastic ROS17/2.8 cell proliferation (25), whereas the low-molecular-weight (LMW)/exported isoform is involved in the prostaglandin F2␣ (PGF2␣) effects found in mouse primary calvarial osteoblasts (26 -28). In addition, we demonstrated that the anabolic effects of PTH on bone are, at least in part, mediated by FGF-2 (29). In other studies we reported that BMP-2 increased FGF-2 mRNA and protein in osteoblasts from Fgf2 ϩ/ϩ mice (30).…”

Fibroblast growth factor signaling in skeletal development and disease

“…effect is dependent in part on FGF2 expression (Sabbieti et al 2009). These genetic and functional analyses support the concept that FGF/FGFR signaling by itself and its interactions with other major signaling pathways play essential roles in controlling osteoblastogenesis and bone formation in adult life.…”