title: Induction of SHP2 deficiency in chondrocytes causes severe scoliosis and kyphosis in mice.
abstract: METHODS
  Genetic engineering techniques were used to develop an animal model of juvenile scoliosis during a postnatal skeletal-growth stage.
  
  
  OBJECTIVE
  To investigate the effect of targeted SHP2 (Src homology-2) deficiency in chondrocytes on the development of scoliosis during a juvenile growth stage in mice.
  
  
  BACKGROUND
  Juvenile idiopathic scoliosis can lead to progressive severe spinal deformity. The pathophysiology and molecular mechanisms responsible for the deformity are unknown. Here, we investigated the role of SHP2 deficiency in chondrocytes as a potential cause of juvenile scoliosis.
  
  
  METHODS
  Genetically engineered mice with inducible deletion of SHP2 in chondrocytes were generated. The SHP2 function in chondrocytes was inactivated during a juvenile growth stage from the mouse age of 4 weeks. Radiographical, micro-computed tomographic, and histological assessments were used to analyze spinal changes.
  
  
  RESULTS
  When SHP2 deficiency was induced during the juvenile stage, a progressive kyphoscoliotic deformity (thoracic lordosis and thoracolumbar kyphoscoliosis) developed within 2 weeks of the initiation of SHP2 deficiency. The 3-dimensional micro-computed tomography analysis confirmed the kyphoscoliotic deformity with a rotational deformity of the spine and osteophyte formation. The histological analysis revealed disorganization of the vertebral growth plate cartilage. Interestingly, when SHP2 was disrupted during the adolescent to adult stages, no spinal deformity developed.
  
  
  CONCLUSIONS
  SHP2 plays an important role in normal spine development during skeletal maturation. Chondrocyte-specific deletion of SHP2 at a juvenile stage produced a kyphoscoliotic deformity. This new mouse model will be useful for future investigations of the role of SHP2 deficiency in chondrocytes as a mechanism leading to the development of juvenile scoliosis.
  
  
  METHODS
  N/A.
authors.affiliation: *Texas Scottish Rite Hospital for Children, Dallas, TX †Orthopaedic Surgery, University of Texas Southwestern Medical Center, Dallas, TX ‡Department of Pathology, and Division of Biological Sciences, University of California San Diego, La Jolla, CA §Department of Biochemistry, Rush University Medical Center, Chicago, IL; and ¶Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI.
authors.forename: Harry K W
authors.initials: HK
authors.lastname: Kim
authors.forename: Olumide
authors.initials: O
authors.lastname: Aruwajoye
authors.forename: Daniel
authors.initials: D
authors.lastname: Sucato
authors.forename: B Stephens
authors.initials: BS
authors.lastname: Richards
authors.forename: Gen-Sheng
authors.initials: GS
authors.lastname: Feng
authors.forename: Di
authors.initials: D
authors.lastname: Chen
authors.forename: Philip D
authors.initials: PD
authors.lastname: King
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Kamiya
mesh_terms: D000818:Animals; D002574:Cervical Vertebrae / Q000000981:diagnostic imaging / Q000378:metabolism; D019902:Chondrocytes / Q000378:metabolism*; D024043:Collagen Type II / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D007738:Kyphosis / Q000235:genetics* / Q000473:pathology; D008141:Lordosis / Q000235:genetics / Q000473:pathology; D008159:Lumbar Vertebrae / Q000000981:diagnostic imaging / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic / Q000235:genetics; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000172:deficiency / Q000235:genetics*; D012600:Scoliosis / Q000235:genetics* / Q000473:pathology; D012720:Severity of Illness Index; D013629:Tamoxifen / Q000494:pharmacology; D013904:Thoracic Vertebrae / Q000000981:diagnostic imaging / Q000378:metabolism; D013997:Time Factors; D055114:X-Ray Microtomography
chemical_list: C447413:Col2a1 protein, mouse; D024043:Collagen Type II; D013629:Tamoxifen; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; C516725:Ptpn11 protein, mouse