Physiology and Pharmacology Publications

Title

Cartilage-specific deletion of Mig-6 results in osteoarthritis-like disorder with excessive articular chondrocyte proliferation

Document Type

Article

Publication Date

2-18-2014

Journal

Proceedings of the National Academy of Sciences of the United States of America

First Page

2590

Last Page

2595

URL with Digital Object Identifier

10.1073/pnas.1400744111

Abstract

A deficiency of mitogen-inducible gene-6 (Mig-6) in mice leads to the development of an early-onset, osteoarthritis (OA)-like disorder in multiple synovial joints, underlying its importance inmaintaining joint homeostasis. Here we determined what joint tissues Mig-6 is expressed in and what role chondrocytes play in the Mig-6-deficient OA-like disorder. AMig-6/lacZ reporter mouse strain expressing B-galactosidase under the control of the Mig-6 gene promoter was generated to determineMig-6 expression in joint tissues. By B-galactosidase staining, we demonstrated that Mig-6 was uniquely expressed in the cells across the entire surface of the synovial joint cavity, including chondrocytes in the superficial zone of articular cartilage and in the meniscus, aswell as synovial lining cells. By crossingMig-6-floxedmice to Col2a1-Cre transgenic mice, to generate cartilage-specific deletion of Mig-6, we demonstrated that deficiency of Mig-6 in the chondrocytes results in a joint phenotype that only partially recapitulates the OA-like disorder of the Mig-6-deficient mice: Ubiquitous deletion of Mig-6 led to the OA-like disorder in multiple joints,whereas cartilagespecific deletion affected the knees but rarely other joints. Furthermore, chondrocytes with Mig-6 deficiency showed excessive proliferative activities along with enhanced EGF receptor signaling in the articular cartilage and in the abnormally formed osteophytes. Our findings provide insight into the crucial requirement forMig-6 in maintaining joint homeostasis and in regulating chondrocyte activities in the synovial joints. Our data also suggest that other cell types are required for fully developing the Mig-6-deficient OA-like disorder.

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