Achondroplasia is the most prevalent genetic form of dwarfism in humans and is caused by activating mutations in FGFR3 tyrosine kinase. The clinical need for a safe and effective inhibitor of FGFR3 is unmet, leaving achondroplasia currently incurable. Here, we evaluated RBM-007, an RNA aptamer previously developed to neutralize the FGFR3 ligand FGF2, for its activity against FGFR3. In cultured rat chondrocytes or mouse embryonal tibia organ culture, RBM-007 rescued the proliferation arrest, degradation of cartilaginous extracellular matrix, premature senescence, and impaired hypertrophic differentiation induced by FGFR3 signaling. In cartilage xenografts derived from induced pluripotent stem cells from individuals with achondroplasia, RBM-007 rescued impaired chondrocyte differentiation and maturation. When delivered by subcutaneous injection, RBM-007 restored defective skeletal growth in a mouse model of achondroplasia. We thus demonstrate a ligand-trap concept of targeting the cartilage FGFR3 and delineate a potential therapeutic approach for achondroplasia and other FGFR3-related skeletal dysplasias.
- MeSH
- achondroplazie * farmakoterapie genetika MeSH
- aptamery nukleotidové * MeSH
- buněčná diferenciace MeSH
- chondrocyty MeSH
- krysa rodu rattus MeSH
- myši MeSH
- receptor fibroblastových růstových faktorů, typ 3 genetika MeSH
- vývoj kostí MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Studies have suggested a role for the mammalian (or mechanistic) target of rapamycin (mTOR) in skeletal development and homeostasis, yet there is no evidence connecting mTOR with the key signaling pathways that regulate skeletogenesis. We identified a parathyroid hormone (PTH)/PTH-related peptide (PTHrP)-salt-inducible kinase 3 (SIK3)-mTOR signaling cascade essential for skeletogenesis. While investigating a new skeletal dysplasia caused by a homozygous mutation in the catalytic domain of SIK3, we observed decreased activity of mTOR complex 1 (mTORC1) and mTORC2 due to accumulation of DEPTOR, a negative regulator of both mTOR complexes. This SIK3 syndrome shared skeletal features with Jansen metaphyseal chondrodysplasia (JMC), a disorder caused by constitutive activation of the PTH/PTHrP receptor. JMC-derived chondrocytes showed reduced SIK3 activity, elevated DEPTOR, and decreased mTORC1 and mTORC2 activity, indicating a common mechanism of disease. The data demonstrate that SIK3 is an essential positive regulator of mTOR signaling that functions by triggering DEPTOR degradation in response to PTH/PTHrP signaling during skeletogenesis.
- MeSH
- HEK293 buňky MeSH
- homozygot MeSH
- intracelulární signální peptidy a proteiny metabolismus MeSH
- lidé MeSH
- mechanistické cílové místo rapamycinového komplexu 1 metabolismus MeSH
- mechanistické cílové místo rapamycinového komplexu 2 metabolismus MeSH
- missense mutace genetika MeSH
- mutantní proteiny chemie metabolismus MeSH
- osteogeneze * MeSH
- parathormon metabolismus MeSH
- protein podobný parathormonu metabolismus MeSH
- proteinkinasy chemie nedostatek genetika metabolismus MeSH
- proteolýza MeSH
- růstová ploténka metabolismus MeSH
- sekvence aminokyselin MeSH
- signální transdukce * MeSH
- TOR serin-threoninkinasy metabolismus MeSH
- typy dědičnosti genetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH