Osteoarthritis-like changes in the heterozygous sedc mouse associated with the HtrA1-Ddr2-Mmp-13 degradative pathway: a new model of osteoarthritis

Osteoarthritis Cartilage. 2012 May;20(5):430-439. doi: 10.1016/j.joca.2011.11.008. Epub 2011 Nov 26.


Objective: To test the hypothesis that the spondyloepiphyseal dysplasia congenita (sedc) heterozygous (sedc/+) mouse, a COL2A1 mutant, is a model for the study of osteoarthritis (OA) in the absence of dwarfism and to investigate the presence of HtrA1, Ddr2, and Mmp-13 and their possible involvement in a universal mechanism leading to OA.

Design: Whole mount skeletons of adult animals were analyzed to determine whether sedc/+ mice exhibit dwarfism. To characterize progression of osteoarthritic degeneration over time, knee and temporomandibular joints from sedc/+ and wild-type mice were analyzed histologically, and severity of articular cartilage degradation was graded using the Osteoarthritis Research Society International (OARSI) scoring system. Immunohistochemistry was used to detect changes in expression of HtrA1, Ddr2, and Mmp-13 in articular cartilage of knees.

Results: As previously reported, the sedc/+ skeleton morphology was indistinguishable from wild type, and skeletal measurements revealed no significant differences. The sedc/+ mouse did, however, show significantly higher OARSI scores in knee (9, 12 and 18 months) and temporomandibular joints at all ages examined. Histological staining showed regions of proteoglycan degradation as early as 2 months in both temporomandibular and knee joints of the mutant. Cartilage fissuring and erosion were observed to begin between 2 and 6 months in temporomandibular joints and 9 months in knee joints from sedc/+ mice. Immunohistochemistry of mutant knee articular cartilage showed increased expression of HtrA1, Ddr2, and Mmp-13 compared to wild type, which upregulation preceded fibrillation and fissuring of the articular surfaces.

Conclusions: With regard to skeletal morphology, the sedc/+ mouse appears phenotypically normal but develops premature OA as hypothesized. We conclude that the sedc/+ mouse is a useful model for the study of OA in individuals with overtly normal skeletal structure and a predisposition for articular cartilage degeneration.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arthritis, Experimental / genetics*
  • Arthritis, Experimental / metabolism
  • Arthritis, Experimental / pathology
  • Cartilage, Articular / metabolism
  • Collagen Type II / genetics
  • Collagen Type VI / metabolism
  • Discoidin Domain Receptors
  • Disease Progression
  • Femur / pathology
  • Genetic Predisposition to Disease
  • High-Temperature Requirement A Serine Peptidase 1
  • Male
  • Matrix Metalloproteinase 13 / metabolism
  • Mice
  • Mice, Mutant Strains
  • Mutation
  • Osteoarthritis / genetics*
  • Osteoarthritis / metabolism
  • Osteoarthritis / pathology
  • Osteochondrodysplasias / congenital*
  • Osteochondrodysplasias / genetics
  • Osteochondrodysplasias / metabolism
  • Osteochondrodysplasias / pathology
  • Receptor Protein-Tyrosine Kinases / metabolism
  • Receptors, Mitogen / metabolism
  • Serine Endopeptidases / metabolism
  • Signal Transduction / physiology
  • Tibia / pathology
  • Up-Regulation


  • Col2a1 protein, mouse
  • Collagen Type II
  • Collagen Type VI
  • Receptors, Mitogen
  • Discoidin Domain Receptors
  • Receptor Protein-Tyrosine Kinases
  • High-Temperature Requirement A Serine Peptidase 1
  • HtrA1 protein, mouse
  • Serine Endopeptidases
  • Matrix Metalloproteinase 13

Supplementary concepts

  • Spondyloepiphyseal dysplasia, congenita