Targeted disruption of Mig-6 in the mouse genome leads to early onset degenerative joint disease.
Degenerative joint disease, also known as osteoarthritis, is the most common joint disorder in human beings. The molecular mechanism underlying this disease is not fully understood. Here, we report that disruption of mitogen-inducible gene 6 (Mig-6) in mice by homologous recombination leads to early onset degenerative joint disease, which is revealed by simultaneous enlargement and deformity of multiple joints, degradation of articular cartilage, and the development of bony outgrowths or osteophyte formation within joint space. The osteophyte formation appears to be derived from proliferation of mesenchymal progenitor cells followed by differentiation into chondrocytes. Absence of the Rag2 gene does not rescue the joint phenotype, excluding a role for the acquired immune system in the development of this disease. Our results provide insight into the mechanism of osteoarthritis by showing that loss of Mig-6 leads to early onset of this disease, implying that this gene or its pathway is important in normal joint maintenance. Because of the striking similarity of osteoarthritis in humans and mice, the Mig-6 mutant mouse should provide a useful animal model for studying the mechanism of this disease and for testing drugs or therapies for treating osteoarthritis.
Zhang
Yu-Wen
YW
Laboratory of Molecular Oncology, Van Andel Research Institute, Grand Rapids, MI 49503, USA.
Su
Yanli
Y
Lanning
Nathan
N
Swiatek
Pamela J
PJ
Bronson
Roderick T
RT
Sigler
Robert
R
Martin
Richard W
RW
Vande Woude
George F
GF
D017668:Age of Onset; D000818:Animals; D049109:Cell Proliferation; D054370:Chemokine CXCL9; D019743:Chemokines, CXC / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D017353:Gene Deletion; D016678:Genome; D006965:Hyperplasia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D007592:Joint Diseases / Q000235:genetics* / Q000473:pathology*; D007596:Joints / Q000002:abnormalities; D059630:Mesenchymal Stem Cells / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D011509:Proteoglycans / Q000378:metabolism
D054370:Chemokine CXCL9; D019743:Chemokines, CXC; C485969:Cxcl9 protein, mouse; D004268:DNA-Binding Proteins; D011509:Proteoglycans; C499308:Rag2 protein, mouse; C064655:V(D)J recombination activating protein 2