title: Deletion of Mecom in mouse results in early-onset spinal deformity and osteopenia.
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 ME(m1)) 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 2weeks, 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 1week 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.
authors: Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, USA; Department of Orthopedics, University of Rochester Medical Center, USA; Department of Biomedical Engineering, University of Rochester Medical Center, USA. Electronic address: sjuneja.phd@gmail.com.
authors: Subhash C
authors: SC
authors: Juneja
authors: Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, USA. Electronic address: alin_vonica@urmc.rochester.edu.
authors: Alin
authors: A
authors: Vonica
authors: Case Western Reserve University, USA. Electronic address: caroline.zeiss@yale.edu.
authors: Caroline
authors: C
authors: Zeiss
authors: Department of Pathology, Yale University, USA. Electronic address: kimberly.lezon-geyda@yale.edu.
authors: Kimberly
authors: K
authors: Lezon-Geyda
authors: Department of Pathology, Yale University, USA. Electronic address: bogdan.yatsula@yale.edu.
authors: Bogdan
authors: B
authors: Yatsula
authors: Case Western Reserve University, USA. Electronic address: drs7@cwru.edu.
authors: David R
authors: DR
authors: Sell
authors: Case Western Reserve University, USA. Electronic address: vmm3@cwru.edu.
authors: Vincent M
authors: VM
authors: Monnier
authors: Department of Pathology, Yale University, USA. Electronic address: sharon.lin@yale.edu.
authors: Sharon
authors: S
authors: Lin
authors: Department of Pathology, Yale University, USA. Electronic address: thomas.ardito@yale.edu.
authors: Thomas
authors: T
authors: Ardito
authors: University of Washington, Seattle, USA. Electronic address: deyre@u.washington.edu.
authors: David
authors: D
authors: Eyre
authors: Department of Orthopedics, University of Rochester Medical Center, USA. Electronic address: david_reynolds@urmc.rochester.edu.
authors: David
authors: D
authors: Reynolds
authors: Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, USA. Electronic address: zhenqiang_yao@urmc.rochester.edu.
authors: Zhenqiang
authors: Z
authors: Yao
authors: Department of Orthopedics, University of Rochester Medical Center, USA; Department of Biomedical Engineering, University of Rochester Medical Center, USA. Electronic address: hani_awad@urmc.rochester.edu.
authors: Hani A
authors: HA
authors: Awad
authors: Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, USA. Electronic address: yhb3508@163.com.
authors: Hongbo
authors: H
authors: Yu
authors: Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, USA. Electronic address: michael_wilson@urmc.rochester.edu.
authors: Michael
authors: M
authors: Wilson
authors: Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, USA. Electronic address: sylvie.honnons@gmail.com.
authors: Sylvie
authors: S
authors: Honnons
authors: Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, USA. Electronic address: brendan_boyce@urmc.rochester.edu.
authors: Brendan F
authors: BF
authors: Boyce
authors: Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, USA. Electronic address: lianping_xing@urmc.rochester.edu.
authors: Lianping
authors: L
authors: Xing
authors: Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, USA. Electronic address: yi_zhang@urmc.rochester.edu.
authors: Yi
authors: Y
authors: Zhang
authors: Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, USA. Electronic address: archibald_perkins@urmc.rochester.edu.
authors: Archibald S
authors: AS
authors: Perkins
mesh_terms: D000818:Animals; D001696:Biomechanical Phenomena; D001851:Bone Diseases, Metabolic / Q000150:complications* / Q000000981:diagnostic imaging / Q000235:genetics / Q000473:pathology*; D003094:Collagen / Q000235:genetics / Q000648:ultrastructure; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005260:Female; D017353:Gene Deletion; D018390:Gene Targeting; D056426:Genetic Loci / Q000235:genetics; D053823:Hedgehog Proteins / Q000235:genetics; D006801:Humans; D007403:Intervertebral Disc / Q000000981:diagnostic imaging / Q000473:pathology; D007738:Kyphosis / Q000151:congenital / Q000000981:diagnostic imaging / Q000235:genetics / Q000473:pathology; D008141:Lordosis / Q000151:congenital / Q000000981:diagnostic imaging / Q000235:genetics / Q000473:pathology; D008159:Lumbar Vertebrae / Q000000981:diagnostic imaging / Q000473:pathology; D000074008:MDS1 and EVI1 Complex Locus Protein; D008297:Male; D051379:Mice; D009154:Mutation / Q000235:genetics; D010012:Osteogenesis; D011519:Proto-Oncogenes; D044168:Receptor, Parathyroid Hormone, Type 1 / Q000235:genetics; D013131:Spine / Q000002:abnormalities* / Q000000981:diagnostic imaging / Q000473:pathology; D013710:Tendons / Q000000981:diagnostic imaging / Q000473:pathology / Q000648:ultrastructure; D013904:Thoracic Vertebrae / Q000000981:diagnostic imaging / Q000473:pathology; D014157:Transcription Factors / Q000378:metabolism*; D055114:X-Ray Microtomography
chemical_list: D004268:DNA-Binding Proteins; D053823:Hedgehog Proteins; D000074008:MDS1 and EVI1 Complex Locus Protein; C499305:Mecom protein, mouse; D044168:Receptor, Parathyroid Hormone, Type 1; D014157:Transcription Factors; C514061:ihh protein, mouse; D003094:Collagen
keywords: Congenital kyphoscoliosis; MDS1-EVI1; Osteoporosis