Transcription Factor Mohawk and the Pathogenesis of Human Anterior Cruciate Ligament Degradation

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Abstract

Objective

To investigate the expression and function of Mohawk (MKX) in human adult anterior cruciate ligament (ACL) tissue and ligament cells from normal and osteoarthritis (OA)–affected knees.

Methods

Knee joints were obtained at autopsy (within 24–48 hours postmortem) from 13 donors with normal knees (mean ± SD age 36.9 ± 11.0 years), 16 donors with knee OA (age 79.7 ± 11.4 years), and 8 aging donors without knee OA (age 76.9 ± 12.9 years). All cartilage surfaces were graded macroscopically. MKX expression was analyzed by immunohistochemistry and quantitative polymerase chain reaction. ACL-derived cells were used to study regulation ofMKXexpression by interleukin-1β (IL-1β).MKXwas knocked down with small interfering RNA (siRNA) to analyze the function ofMKXin extracellular matrix (ECM) production and differentiation in ACL-derived cells.

Results

The expression ofMKXwas significantly decreased in ACL-derived cells from OA knees compared with normal knees. Consistent with this finding, immunohistochemistry analysis showed that MKX-positive cells were significantly reduced in ACL tissue from OA donors, in particular in cells located in disorientated fibers. In ACL-derived cells, IL-1β strongly suppressedMKXexpression and reduced expression of the ligament ECM genesCOL1A1andTNXB. In contrast,SOX9, a chondrocyte master transcription factor, was up-regulated by IL-1β treatment. Importantly, knockdown ofMKXexpression with siRNA up-regulatedSOX9expression in ACL-derived cells, whereas the expression ofCOL1A1andTNXBwas reduced.

Conclusion

Reduced expression of MKX is a feature of degenerated ACL in OA-affected joints, and this may be mediated in part by IL-1β. MKX appears necessary to maintain the tissue-specific cellular differentiation status and ECM production in adult human tendons and ligaments.

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