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An antibody to Notch3 reverses the skeletal phenotype of lateral meningocele syndrome in male mice.

ABSTRACT: 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.

SUBMITTER: Yu J

PROVIDER: S-EPMC6778702 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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An antibody to Notch3 reverses the skeletal phenotype of lateral meningocele syndrome in male mice.

Yu Jungeun J Siebel Christian W CW Schilling Lauren L Canalis Ernesto E

Journal of cellular physiology 20190612 1

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<sup>tm1.1Ecan</sup> ) 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<sup>tm1.1Ecan</sup> mice exhibit osteopenia. The cancellous bone osteopenia was no longer o ...[more]

PMID: 31188489

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An antibody to Notch3 reverses the skeletal phenotype of lateral meningocele syndrome in male mice.

Publications

An antibody to Notch3 reverses the skeletal phenotype of lateral meningocele syndrome in male mice.

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