Fibroblast Growth Factor 2 and Its Receptors in Bone Biology and Disease

Abstract

The fibroblast growth factor (FGF) regulatory axis is phylogenetically ancient, evolving into a large mammalian/human gene family of 22 ligands that bind to four receptor tyrosine kinases for a complex physiologic system controlling cell growth, differentiation, and metabolism. The tissue targets for the primary FGF function are mainly in cartilage and in bone for morphogenesis, mineralization, and metabolism. A multitude of complexities in the FGF ligand-receptor signaling pathways have made translation into therapies for FGF-related bone disorders such as osteomalacia, osteoarthritis, and osteoporosis difficult but not impossible.

Osteocyte Death and Bone Overgrowth in Mice Lacking Fibroblast Growth Factor Receptors 1 and 2 in Mature Osteoblasts and Osteocytes

“…The FGF ligands that function in neonatal and juvenile growing bone are not known. FGF2, FGF9, and FGF18 are good candidates because FGF9 and FGF18 have established roles in bone development, and FGF2 has established roles in growing and mature bone . However, loss of FGF2 leads to osteoporosis, suggesting that it functions at a different stage of the osteoblast lineage or functions through a different FGFR, such as FGFR3, which is also expressed in mature osteoblasts.…”

“…FGF2, FGF9, and FGF18 are good candidates because FGF9 and FGF18 have established roles in bone development, (34,(77)(78)(79)(80)(81)(82)(83)(84) and FGF2 has established roles in growing and mature bone. (85) However, loss of FGF2 leads to osteoporosis, suggesting that it functions at a different stage of the osteoblast lineage or functions through a different FGFR, such as FGFR3, which is also expressed in mature osteoblasts. Future experiments will be required to determine if there is redundancy between FGF2 and FGF9/18 or unique stagespecific activities of these ligands during osteoblast maturation in growing bone.…”

Osteocyte death and bone overgrowth in mice lacking Fibroblast Growth Factor Receptors 1 and 2 in mature osteoblasts and osteocytes

“…FGF2, FGF9, and FGF18 are good candidates since FGF9 and FGF18 have established roles in bone development, (33,(74)(75)(76)(77)(78)(79)(80)(81) and FGF2 has established roles in growing and mature bone. (82) However, loss of FGF2 leads to osteoporosis, suggesting that it functions at a different stage of the osteoblast lineage, or functions through a different FGFR, such as FGFR3, which is also expressed in mature osteoblasts. Future experiments will be required to determine if there is redundancy between FGF2 and FGF9/18, or unique stage-specific activities of these ligands during osteoblast maturation in growing bone.…”

FGF/FGFR signaling in health and disease

“…The HMW FGF2 has an inhibitory effect on bone mineralization, while the LMW FGF2 promotes bone formation through the regulation of Wnt, BMP2, FGF23, and phosphate homeostasis. 152 , 153 In the articular cartilage, FGF2 binds to perlecan in the pericellular matrix and acts as a mechanotransducer. 154 Full-length FGF2 or LMW FGF2 ablation in mice leads to early onset of osteoarthritis (OA), whereas loss of HMW FGF2 isoform has a protective effect on the articular cartilage.…”