ROR2-Related Skeletal Dysplasia Reveals Disrupted Chondrocyte Polarity through Modulation of BMP/TGF-β Signaling

Genetic studies have shown that Robinow syndrome (RS), a rare skeletal dysplasia, is caused by ROR2 mutation. However, the cell origin and molecular mechanisms underlying this disease remain elusive. We established a conditional knockout system by crossing Prx1cre and Osxcre with Ror2 mice. and cond...

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Bibliographic Details
Published in:Aging and disease 2024-02, Vol.15 (1), p.282-294
Main Authors: Yao, Yichen, Wang, Xin, Lin, Lichieh, Zhang, Xiaolei, Wang, Yan
Format: Article
Language:English
Subjects:
Animals
Cell Differentiation - genetics
Chondrocytes
Craniofacial Abnormalities
Dwarfism
Limb Deformities, Congenital
Mice
Original
Osteoblasts
Osteogenesis - genetics
Transforming Growth Factor beta - metabolism
Urogenital Abnormalities
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Summary:Genetic studies have shown that Robinow syndrome (RS), a rare skeletal dysplasia, is caused by ROR2 mutation. However, the cell origin and molecular mechanisms underlying this disease remain elusive. We established a conditional knockout system by crossing Prx1cre and Osxcre with Ror2 mice. and conducted histological and immunofluorescence analyses to investigate the phenotypes during skeletal development. In the Prx1cre line, we observed RS-like skeletal abnormities, including short stature and an arched skull. Additionally, we found inhibition of chondrocyte differentiation and proliferation. In the Osxcre line, loss of ROR2 in osteoblast lineage cells led to reduced osteoblast differentiation during both embryonic and postnatal stages. Furthermore, ROR2 mutant mice exhibited increased adipogenesis in the bone marrow compared to their littermate controls. To further explore the underlying mechanisms, bulk RNA-seq analysis of Prx1cre; Ror2 embryos was performed, results revealed decreased BMP/TGF-β signaling. Immunofluorescence analysis further confirmed the decreased expression of p-smad1/5/8, accompanied by disrupted cell polarity in the developing growth plate. Pharmacological treatment using FK506 partially rescued the skeletal dysplasia and resulted in increased mineralization and osteoblast differentiation. By modeling the phenotype of RS in mice, our findings provide evidence for the involvement of mesenchymal progenitors as the cell origin and highlight the molecular mechanism of BMP/TGF-β signaling in skeletal dysplasia.
ISSN:2152-5250
2152-5250
DOI:10.14336/AD.2023.0531