RECENT RESEARCH ON THE GROWTH PLATE: Advances in fibroblast growth factor signaling in growth plate development and disorders

Abstract

Skeletons are formed through two distinct developmental actions, intramembranous ossification and endochondral ossification. During embryonic development, most bone is formed by endochondral ossification. The growth plate is the developmental center for endochondral ossification. Multiple signaling pathways participate in the regulation of endochondral ossification. Fibroblast growth factor (FGF)/FGF receptor (FGFR) signaling has been found to play a vital role in the development and maintenance of growth plates. Missense mutations in FGFs and FGFRs can cause multiple genetic skeletal diseases with disordered endochondral ossification. Clarifying the molecular mechanisms of FGFs/FGFRs signaling in skeletal development and genetic skeletal diseases will have implications for the development of therapies for FGF-signaling-related skeletal dysplasias and growth plate injuries. In this review, we summarize the recent advances in elucidating the role of FGFs/FGFRs signaling in growth plate development, genetic skeletal disorders, and the promising therapies for those genetic skeletal diseases resulting from FGFs/FGFRs dysfunction. Finally, we also examine the potential important research in this field in the future.

SWI/SNF-Mediated Lineage Determination in Mesenchymal Stem Cells Confers Resistance to Osteoporosis

“…Vertebrates express at least 22 different FGF ligands, and at least half of these can signal through FGFR2. Ligand‐mediated activation of the receptor in vivo depends on the balance of FGFs, and on the distinct timing and location of their expression patterns 38, 39. Increased expression of FGFR2 with BRM deficiency is consistent across the two independently generated knockdown lines and the primary cell model.…”

Fibroblast Growth Factor Receptor 3 Inhibits Osteoarthritis Progression in the Knee Joints of Adult Mice

“…FGFs exert their effects by binding to FGF receptors (FGFRs) (5), which are expressed in specific spatio-temporal expression patterns in the developing and adult skeletons. For example, FGFR3 is initially expressed by chondrocytes located in the central core of mesenchymal condensation during early development, then in proliferating and pre-hypertrophic zones of growth plates and articular chondrocytes (6). Mutations in FGFR3 have been linked to a variety of human genetic skeletal dysplasias: gain-of-function mutations in FGFR3 result in chondrodysplasias, including achondroplasia (ACH), hypochondroplasia, and thanatophoric dysplasia (TD), while loss-of-function mutations of FGFR3 lead to camptodactyly, tall stature, scoliosis, and hearing loss syndrome in humans (7,8).…”

Chondrocyte FGFR3 Regulates Bone Mass by Inhibiting Osteogenesis

“…Fibroblast growth factor receptor 3 (FGFR3) is one of a family of four membrane-bound receptor tyrosine kinases (FGFR1-4) linked to downstream pathways including MAPK, PKC-␥, PI3K/AKT, and STAT signaling pathways (14). FGFR3 is highly expressed in chondrocytes of growth plates (15)(16)(17)(18), and is a negative regulator of endochondral bone development (4,14). Gain-of-function mutations in FGFR3 lead to chondrodysplasias including achondroplasia (ACH), hypochondroplasia (HCH), and thanatophoric dysplasia (TD).…”