Targeted disruption of Mig-6 in the mouse genome leads to early onset degenerative joint disease

Abstract

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.animal model ͉ mutation ͉ osteoarthritis ͉ bony outgrowth ͉ signaling pathway D egenerative joint disease, or osteoarthritis, affects nearly 12% of the population between ages 25 and 74 in the United States (1) and greatly interferes with quality of life by causing acute and chronic pain and disability (2, 3). The characteristic features of this disease are joint pain, stiffness, joint enlargement and malalignment, damage of articular cartilage, and formation of osteophytes or bony outgrowths at the margin of the synovial and cartilage junctions (2, 3). Currently, therapy is directed toward controlling symptoms, and no disease-modifying or chondroprotective treatment is available (2, 3). In addition, the costs for pain relief medication are astronomical. Although several genetic and biomechanical factors, including heredity, obesity, injury and joint overuse, are thought to contribute to the development of osteoarthritis (2, 3), the molecular mechanism underlying this disease is still elusive.Mitogen-inducible gene 6 (Mig-6), also known as gene 33, is an immediate early response gene that can be induced by many growth factors or stressful stimuli (4, 5). It has also been shown to act as a negative feedback inhibitor in EGF receptor signaling through direct interaction with EGF receptor family (5-7), and, similarly, the gene is induced by hepatocyte growth factor͞ scatter factor by means of the receptor tyrosine kinase Met (data not shown). To understand its role during mouse development and homeostasis, we generated Mig-6-deficient mice and demonstrated that Mig-6 is essential for normal joint maintenance and that loss of Mig-6 leads to early onset degenerative joint disease. Materials and MethodsMice and Genotyping. To generate Mig-6 knockout mice, we constr...

Evidence that MIG-6 is a tumor-suppressor gene

“…Likewise, Mig-6 may also function as a tumor-suppressor in other organs, since animals with a Mig-6 deficiency also develop gallbladder and bile duct cancers ( Figure 5 and Table 3). Very recently, another group also reported that Mig-6 deficiency in mice caused skin cancer in addition to the joint phenotype that we have previously reported (Zhang et al, 2005;Ferby et al, 2006). Moreover, it has recently been reported that MIG-6 expression is lost in ErbB2-amplified breast carcinomas (Anastasi et al, 2005).…”

“…We disrupted the Mig-6 gene in mice by gene targeting technology and previously reported that loss of Mig-6 leads to early onset degenerative joint disease (Zhang et al, 2005). Although Mig-6 is expressed in mouse lung tissue, we did not observe developmental lung defects at early stages of development in Mig-6-deficient mice (data not shown).…”

“…However, from 5 to 13 months we observed that Mig-6 mutant mice develop lung abnormalities, ranging from epithelial hyperplasia of bronchi and bronchiole to the formation of adenomas or adenocarcinomas ( Figure 4 and Table 2). A majority of Mig-6 mutant mice die within 6 months due to the joint abnormality (Zhang et al, 2005), and out of a total of 29 Mig-6 À/À mice between 5 and 13 months, we observed four lung cancers; one animal had an adenocarcinoma, a second animal had two adenomas in two different lobes, and two mice with a single adenoma each. In addition, in the 29 homozygous animals we observed 11 cases of bronchi or bronchiole epithelial hyperplasia (Table 2).…”

“…Mig-6 may provide a checkpoint for normal cell proliferation in certain tissues; disruption of Mig-6 leads to uncontrolled proliferation of cells as revealed by PCNA staining in gallbladder epithelium ( Figure 5) and in joint tissues (Zhang et al, 2005). A role for MIG-6 in cell cycle regulation has also been implied, as its expression is regulated during the normal cell cycle progression (Wick et al, 1995).…”

“…The generation and genotyping of Mig-6 knockout mice has been described elsewhere (Zhang et al, 2005). The mice analysed in this study are on a B6/129 background.…”