Osteoclastic bone resorption through receptor tyrosine kinase and extracellular signal-regulated kinase signaling in mature osteoclasts

Abstract

It has recently been suggested that signaling through receptor tyrosine kinases (RTKs) expressed on mature osteoclasts is involved in osteoclastic bone resorption. This study investigated the role and mechanism of two major RTKs expressed on mature osteoclasts, fibroblast growth factor receptor type 1 (FGFR1) and Tyro 3. Among the FGF receptors (FGFR1-4), only FGFR1 was detected on isolated mouse osteoclasts, while all FGFRs were identified on mouse osteoblasts. Tyro 3 was seen only in mature osteoclasts among bone cells. FGF-2 moderately stimulated pit formation by isolated rabbit osteoclasts at low concentrations (>==10(-12) M), whereas at high concentrations (>==10(-9) M) it strongly stimulated pit formation by unfractionated bone cells. Gas6, the ligand of Tyro 3, was expressed ubiquitously in bone cells and stimulated osteoclast function to form resorbed pits on a dentine slice. Both FGF-2 and Gas6 upregulated the phosphorylation of cellular proteins, including extracellular signal-regulated kinase (ERK), and increased the kinase activity of immunoprecipitated FGFR1 and Tyro 3, respectively, in mouse osteoclasts. The stimulation of these cytokines on mouse and rabbit osteoclast functions was abrogated by PD98059, a specific inhibitor of ERK. These results strongly suggest that these cytokines act directly on mature osteoclasts through the activation of RTKs and ERK, causing the stimulation of bone resorption.

Vitamin K‐Dependent Actions of Gas6

“…Vascular pericytes undergo osteogenic differentiation in vivo which may be implicated in diseases involving ectopic calcification and osteogenesis, a process that was inhibited by Gas6/Axl signaling (Collett et al 2003). This effect is not completely surprising considering several reports implicating the Gas6/TAM system in osteoclast function (Nakamura et al 1998;Katagiri et al 2001;Kawaguchi et al 2004). It has recently been reported that the induction of calcification of cultured VSMCs is inhibited by Axl (Collett et al 2007), and the reversion of the process by statins was also mediated by activation of the Gas6/Axl pathway (Son et al 2006;Son et al 2007).…”

Single nucleotide polymorphisms in new candidate genes are associated with bone mineral density and fracture risk

“…Three individual SNPs associated with osteoporotic phenotypes have been identified in this study. FGFR1 (member of receptor tyrosine kinases) is expressed on both osteoclasts and osteoblasts, and influences osteogenic differentiation of stem cells (23)(24)(25). Its mutations and haplotypes are associated with skeletal deformities seen in Pfeiffer and Kallmann syndromes, human tooth agenesis (26), and normal variations in craniofacial shape (27).…”

Osteoclasts and odontoclasts: signaling pathways to development and disease

“…Ron/Stk RTK and its ligand macrophage‐stimulating protein (MSP) directly promote osteoclast resorptive activity through alterations in cytoplasmic contraction, ruffled border formation, redistribution of Src and pit formation rather than via actions on osteoclastogenesis (Fuller et al , 1993; Kurihara et al , 1996). Similarly, Tyro 3 and its ligand Gas6 or protein S can also directly activate osteoclasts through the ERK (Kawaguchi et al , 2004) MAPK p42/44 pathway and lead to pit formation (Katagiri et al , 2001). Among the receptor tyrosine kinases, Tyro 3 is unique because it is expressed only in mature osteoclasts and rarely in hematopoietic stem cells or osteoclast progenitor cells, indicating its action relative to mature osteoclast activation rather than osteoclastogenesis (Nakamura et al , 1998b).…”