FGF signaling in the osteoprogenitor lineage non-autonomously regulates postnatal chondrocyte proliferation and skeletal growth

Abstract

Fibroblast growth factor (FGF) signaling is important for skeletal development; however, cell-specific functions, redundancy and feedback mechanisms regulating bone growth are poorly understood. FGF receptors 1 and 2 (Fgfr1 and Fgfr2) are both expressed in the osteoprogenitor lineage. Double conditional knockout mice, in which both receptors were inactivated using an osteoprogenitor-specific Cre driver, appeared normal at birth; however, these mice showed severe postnatal growth defects that include an ∼50% reduction in body weight and bone mass, and impaired longitudinal bone growth. Histological analysis showed reduced cortical and trabecular bone, suggesting cellautonomous functions of FGF signaling during postnatal bone formation. Surprisingly, the double conditional knockout mice also showed growth plate defects and an arrest in chondrocyte proliferation. We provide genetic evidence of a non-cell-autonomous feedback pathway regulating Fgf9, Fgf18 and Pthlh expression, which led to increased expression and signaling of Fgfr3 in growth plate chondrocytes and suppression of chondrocyte proliferation. These observations show that FGF signaling in the osteoprogenitor lineage is obligately coupled to chondrocyte proliferation and the regulation of longitudinal bone growth.

Elevated Fibroblast Growth Factor Signaling Is Critical for the Pathogenesis of the Dwarfism in Evc2/Limbin Mutant Mice

“…On the other hand, we detected both elevated Fgfr3 expression (Fig 4C) in the growth plate as well as elevated Fgf18 expression in the perichondrium of Evc2 mutants (Fig 4D, 4E and 4F). Previous reports [15, 37] and our current work suggest that PTHrP negatively regulates Fgfr3 expression (S6 Fig). Therefore, elevated Fgfr3 expression in the growth plate is possibly due to decreased Pthrp expression caused by compromised Hedgehog signaling.…”

“…The increased Fgfr3 expression is also supported by the in situ hybridization of Fgfr3 in the embryonic limbs (S5B Fig). It was previously observed that PTH/PTHrP treatment could repress Fgfr3 expression in a chondrocyte cell line in vitro [37] and in growth plate chondrocytes in vivo [15]. As a direct target of Hedgehog signaling in the growth plate, Pthrp expression was decreased in Evc2 mutants (Fig 2A), an effect that may lead to derepression of Fgfr3 expression.…”

“…Indian Hedgehog is synthesized by pre-hypertrophic chondrocytes [13] and stimulates PTHrP synthesis in chondrocytes at the distal end of the growth plate [14]. PTHrP promotes proliferation of chondrocytes and prevents them from progressing to pre-hypertrophic differentiation directly [14] and through suppression of FGF receptor 3 ( Fgfr3 ) expression [15]. Once proliferating chondrocytes are far away enough from the source of PTHrP, they differentiate into pre-hypertrophic chondrocytes, start synthesizing Indian Hedgehog, and then further mature into hypertrophic cells.…”

Achondroplasia: Development, pathogenesis, and therapy

“…Fgfr3 is expressed in proliferating and prehypertrophic chondrocytes during embryonic and postnatal development (Figure 1C) (Peters et al, 1993; Delezoide et al, 1998; Monsonego-Ornan et al, 2000; Pandit et al, 2002; Barnard et al, 2005; Karuppaiah et al, 2016). During establishment of the growth plate before formation of the secondary ossification center, FGFR3 signaling promotes chondrocyte proliferation (Iwata et al, 2000; Iwata et al, 2001; Havens et al, 2008).…”

Signaling pathways regulating cartilage growth plate formation and activity

“…On the other hand, overexpression of Fgfr1 in chondrocytes causes joint fusion. Deletion of both Fgfr1 and Fgfr2 in mice using an Osx-Cre driver caused a decreased length of the growth plate with a reduced number of proliferating chondrocytes [46]. Interestingly, the inactivation of Fgfr1/2 resulted in suppression of Ihh and Pthrp , and the growth plate phenotype was rescued by administration of PTH(1–34), suggesting an in vivo link between FGF signaling and IHH signaling in relaying information between growth plate chondrocytes [46].…”