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

Autor: Robert E. Seegmiller, D.W. Holt, David L. Kooyman, Laura C. Bridgewater, J.T. Farrell, C.E. Stockdale, Michael L Henderson
Rok vydání: 2011
Předmět:
Cartilage
Articular
Male
Pathology
Arthritis
Dwarfism
Osteoarthritis
Type II collagen mutation
Mice
0302 clinical medicine
Mmp-13
Orthopedics and Sports Medicine
Femur
Ddr2
0303 health sciences
Serine Endopeptidases
High-Temperature Requirement A Serine Peptidase 1
Up-Regulation
medicine.anatomical_structure
030220 oncology & carcinogenesis
Spondyloepiphyseal dysplasia congenita
Disease Progression
Immunohistochemistry
Cartilage degradation
Signal Transduction
musculoskeletal diseases
medicine.medical_specialty
Biomedical Engineering
Collagen Type VI
Osteochondrodysplasias
03 medical and health sciences
Rheumatology
Matrix Metalloproteinase 13
medicine
Animals
Genetic Predisposition to Disease
Tibia
Collagen Type II
Discoidin Domain Receptors
030304 developmental biology
business.industry
Cartilage
Receptor Protein-Tyrosine Kinases
medicine.disease
Arthritis
Experimental
Mice
Mutant Strains
Receptors
Mitogen
HtrA1
HTRA1
Mutation
business
Zdroj: Osteoarthritis and cartilage. 20(5)
ISSN: 1522-9653
Popis: Summary 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.
Databáze: OpenAIRE
Externí odkaz: