Deletion of Mecom in mouse results in early-onset spinal deformity and osteopenia

• Published in: Bone (New York, N.Y.) N.Y.), 2014-03, Vol.60, p.148-161
• Main Authors: Juneja, Subhash C, Vonica, Alin, Zeiss, Caroline, Lezon-Geyda, Kimberly, Yatsula, Bogdan, Sell, David R, Monnier, Vincent M, Lin, Sharon, Ardito, Thomas, Eyre, David, Reynolds, David, Yao, Zhenqiang, Awad, Hani A, Yu, Hongbo, Wilson, Michael, Honnons, Sylvie, Boyce, Brendan F, Xing, Lianping, Zhang, Yi, Perkins, Archibald S
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Biomechanical Phenomena; Bone Diseases, Metabolic - complications; Bone Diseases, Metabolic - diagnostic imaging; Bone Diseases, Metabolic - genetics; Bone Diseases, Metabolic - pathology; Collagen - genetics; Collagen - ultrastructure; Congenital kyphoscoliosis; Diseases of the osteoarticular system; Diseases of the spine; DNA-Binding Proteins - metabolism; Female; Fundamental and applied biological sciences. Psychology; Gene Deletion; Gene Targeting; Genetic Loci - genetics; Hedgehog Proteins - genetics; Humans; Intervertebral Disc - diagnostic imaging; Intervertebral Disc - pathology; Kyphosis - congenital; Kyphosis - diagnostic imaging; Kyphosis - genetics; Kyphosis - pathology; Lordosis - congenital; Lordosis - diagnostic imaging; Lordosis - genetics; Lordosis - pathology; Lumbar Vertebrae - diagnostic imaging; Lumbar Vertebrae - pathology; Male; MDS1 and EVI1 Complex Locus Protein; MDS1-EVI1; Medical sciences; Mice; Mutation - genetics; Orthopedics; Osteogenesis; Osteoporosis; Osteoporosis. Osteomalacia. Paget disease; Proto-Oncogenes; Receptor, Parathyroid Hormone, Type 1 - genetics; Spine - abnormalities; Spine - diagnostic imaging; Spine - pathology; Tendons - diagnostic imaging; Tendons - pathology; Tendons - ultrastructure; Thoracic Vertebrae - diagnostic imaging; Thoracic Vertebrae - pathology; Transcription Factors - metabolism; Vertebrates: anatomy and physiology, studies on body, several organs or systems; X-Ray Microtomography
• ISSN: 8756-3282; 1873-2763
• DOI: 10.1016/j.bone.2013.11.020

Abstract Recent studies have indicated a role for a MECOM allele in susceptibility to osteoporotic fractures in humans. We have generated a mutation in Mecom in mouse (termed MEm1 ) via lacZ knock-in into the upstream transcription start site for the gene, resulting in disruption of Mds1 and Mds1 - Evi1 transcripts, but not of Evi1 transcripts. We demonstrate that ME m1 / m1 mice have severe kyphoscoliosis that is reminiscent of human congenital or primary kyphoscoliosis. ME m1 / m1 mice appear normal at birth, but by 2 weeks, they exhibit a slight lumbar lordosis and narrowed intervertebral space. This progresses to severe lordosis with disc collapse and synostosis, together with kyphoscoliosis. Bone formation and strength testing show that ME m1 / m1 mice have normal bone formation and composition but are osteopenic. While endochondral bone development is normal, it is markedly dysplastic in its organization. Electron micrographs of the 1 week postnatal intervertebral discs reveals marked disarray of collagen fibers, consistent with an inherent weakness in the non-osseous connective tissue associated with the spine. These findings indicate that lack of ME leads to a complex defect in both osseous and non-osseous musculoskeletal tissues, including a marked vertebral osteopenia, degeneration of the IVD, and disarray of connective tissues, which is likely due to an inherent inability to establish and/or maintain components of these tissues.