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An antibody to Notch3 reverses the skeletal phenotype of lateral meningocele syndrome in male mice
Author(s) -
Yu Jungeun,
Siebel Christian W.,
Schilling Lauren,
Canalis Ernesto
Publication year - 2020
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.28960
Subject(s) - osteopenia , mutant , osteoblast , antibody , hes1 , chemistry , medicine , microbiology and biotechnology , endocrinology , osteoporosis , notch signaling pathway , receptor , biology , gene , immunology , bone mineral , biochemistry , in vitro
Lateral meningocele syndrome (LMS), a genetic disorder characterized by meningoceles and skeletal abnormalities, is associated with NOTCH3 mutations. We created a mouse model of LMS ( Notch3 tm1.1Ecan ) by introducing a tandem termination codon in the Notch3 locus upstream of the proline (P), glutamic acid (E), serine (S) and threonine (T) domain. Microcomputed tomography demonstrated that Notch3 tm1.1Ecan mice exhibit osteopenia. The cancellous bone osteopenia was no longer observed after the intraperitoneal administration of antibodies directed to the negative regulatory region (NRR) of Notch3. The anti‐Notch3 NRR antibody suppressed the expression of Hes1 , Hey1 , and Hey2 (Notch target genes), and decreased Tnfsf11 (receptor activator of NF Kappa B ligand) messenger RNA in Notch3 tm1.1Ecan osteoblast (OB) cultures. Bone marrow‐derived macrophages (BMMs) from Notch3 tm1.1Ecan mutants exhibited enhanced osteoclastogenesis in culture, and this was increased in cocultures with Notch3 tm1.1Ecan OB. Osteoclastogenesis was suppressed by anti‐Notch3 NRR antibodies in Notch3 tm1.1Ecan OB/BMM cocultures. In conclusion, the cancellous bone osteopenia of Notch3 tm1.1Ecan mutants is reversed by anti‐Notch3 NRR antibodies.