Advances in the mechanism and therapies of achondroplasia

Abstract

Achondroplasia (ACH), is the prevailing type of genetic dwarfism in humans, caused by mutations in fibroblast growth factor receptor 3 (FGFR3) that are inherited in an autosomal dominant manner. FGFR3 is mainly expressed in condensed mesenchyme, chondrocytes, and mature osteoblasts and osteoclasts, in which it regulates the formation, development, growth, and remodeling of the skeletal system. Mutations in FGFR3 causing ACH result in enhanced FGFR3 signaling through combined mechanisms including enhancing FGF dimerization and tyrosine kinase activity and stabilizing FGF receptors. In ACH, suppression of the proliferation and maturation of chondrocytes in the growth plate leads to a notable reduction in growth plate size, trabecular bone volume, and bone elongation through a profound enhancement of FGFR3 signaling. This review aims to comprehensively outline the cellular and molecular mechanisms contributing to the pathological process of ACH and its potential therapeutic interventions.

Keywords: Achondroplasia; FGFR3; Mechanisms; Skeleton development; Therapeutic interventions.

Figure 1

The mutational spectrum of fibroblast growth factor receptor 3 (FGFR3) in individuals with achondroplasia. In humans, the mutations associated with achondroplasia patients are mainly located in transmembrane (TM) domain of FGFR3. The extracellular domain is referred to as ECD, while the intracellular domain is referred to as ICD. Heparan sulfate is represented by HS, and immunoglobulin-like domains are represented by I, II, and III. Tyrosine kinase domains are represented by TK.

Figure 2

Treatment strategies for achondroplasia. FGF ligands initiate the activation of FGFR3 through the process of dimerization and transphosphorylation (P) in the intracellular kinase domain. When FGFR3 is activated, it recruits adaptor molecules (FRS2, SHP2, GRB2) that facilitate the recruitment of guanine nucleotide exchange factor SOS1 to RAS, leading to the activation of the RAS/ERK signaling module. The current therapeutic drugs under clinical evaluation for achondroplasia aim to down-regulate FGFR3 signaling through various mechanisms, such as neutralizing FGF ligands (recifercept, RBM-007), inhibiting FGFR3 catalytic activity (infigratinib), or directly inhibiting the RAS-ERK pathway (meclozine). On the other hand, TransCon CNP and vosoritide function as stable ligands within CNP pathway, effectively impeding the FGFR3 pathway through the facilitation of PKG2-mediated inhibitory phosphorylation of RAF. The potential of anti-FGFR3 antibodies lies in their ability to hinder the interaction between FGF and its receptor site or prevent FGFR3 dimer formation, whereas statins facilitate the degradation of FGFR3. FGFR3, fibroblast growth factor receptor 3; FGF, fibroblast growth factor; FRS2, fibroblast growth factor receptor substrate 2; SHP2, Src homology region 2-containing protein tyrosine phosphatase 2; GRB2, growth factor receptor bound protein 2; SOS1, son of sevenless homolog 1; CNP, C-type natriuretic peptide; PKG2, protein kinase G2; cGMP, cyclic guanosine monophosphate; PTH, parathyroid hormone; NPRB, natriuretic peptide receptor type B; MAPK, mitogen-activated protein kinase.