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Review
. 2020 Mar 3:11:2042018820904016.
doi: 10.1177/2042018820904016. eCollection 2020.

New perspectives on the treatment of skeletal dysplasia

Pauline Marzin  1 , Valérie Cormier-Daire  2
Affiliations
Review

New perspectives on the treatment of skeletal dysplasia

Pauline Marzin et al. Ther Adv Endocrinol Metab. .

Abstract

The last few decades have been marked by the identification of numerous genes implicated in genetic disorders, helping in the elucidation of the underlying pathophysiology of these conditions. This has allowed new therapeutic approaches to emerge such as cellular therapy, gene therapy, or pharmacological therapy for various conditions. Skeletal dysplasias are good models to illustrate these scientific advances. Indeed, several therapeutic strategies are currently being investigated in osteogenesis imperfecta; there are ongoing clinical trials based on pharmacological approaches, targeting signaling pathways in achondroplasia and fibrodysplasia ossificans progressiva or the endoplasmic reticulum stress in metaphyseal dysplasia type Schmid or pseudoachondroplasia. Moreover, the treatment of hypophosphatasia or Morquio A disease illustrates the efficacy of enzyme drug replacement. To provide a highly specialized multidisciplinary approach, these treatments are managed by reference centers. The emergence of treatments in skeletal dysplasia provides new perspectives on the prognosis of these severe conditions and may change prenatal counseling in these diseases over the coming years.

Keywords: achondroplasia; clinical trials; endoplasmic reticulum stress; fibrodysplasia ossificans progressiva; osteogenesis imperfecta.

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Conflict of interest statement

Conflict of interest statement: The authors declare no conflict of interest.

Figures

Figure 1.
Figure 1.
Schematic representation of therapeutic approaches for osteogenesis imperfecta. (1) Bisphosphonates inhibit osteoclastic function. (2) Denosumab links RANKL, preventing the interaction with its receptor, RANK, on osteoclasts and osteoclasts precursors leading to inhibition of osteoclast formation and function. (3) Scl-Ab prevents binding of sclerostin to LRP5/6 and Frizzled coreceptors, thus inhibition of the Wnt/β-catenin signaling pathway. (4) Fresolimumab links TGF-β leading to beneficiary effects in bone remodeling. BPs, denosumab, and fresolimumab decrease bone resorption. Anti-sclerostin and fresolimumab increase bone formation. BPs, bisphosphonates; Fzld, Frizzled; HSC, hematopoietic stem cells; MSC, mesenchymal stroma cells; OPG, osteoprotegerin; RANK, receptor activator of nuclear factor κB; RANKL, receptor activator of nuclear factor κB ligand; Slc-Ab, sclerostin Antibodies; TGF-β, transforming growth factor-beta.
Figure 2.
Figure 2.
Schematic representation of therapeutic approaches for achondroplasia. (1) Stabilized CNP (BMN-111) links NPR2 and thus inhibits RAF activation through protein kinase II activated by a guanylyl cyclase. (2) Statin induces degradation of FGFR3. (3) Tyrosine kinase inhibitors block receptor transphosphorylation of key tyrosine residues within the receptors’ kinase domain. (4) Anti-FGFR3 antibodies (Anti-FGFR3-ab) block FGF binding to the receptor and, thus, its dimerization. (5) PTH increases chondrocyte proliferation and inhibits FGFR3 expression. (6) Soluble FGFR3 (sFGFR3) decoy binds and sequesters FGF ligands. (7) Meclozine attenuates ERK phosphorylation and, thus, decreases RAS pathway hyperactivation. cGMP, cyclic guanosine monophosphate; CNP, C-type natriuretic peptide; FGFR3, fibroblast growth factor receptor type 3; FGF, fibroblast growth factor; NPR2, natriuretic peptide receptor 2; PKD I, protein kinase I; PTH, parathormone.
Figure 3.
Figure 3.
Schematic representation of therapeutic approaches in fibrodysplasia ossificans progressiva. Palovarotene binds RARγ that inhibits Smad phosphorylation and promotes the degradation of phosphorylated Smad1/5/8. Anti-activin antibody (REGN2477) binds and sequesters activin, inhibiting ACVR1 activation. ACVR1, activin receptor type IA.
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