Transcription factor Mohawk and the pathogenesis of human anterior cruciate ligament degradation

Arthritis Rheum. 2013 Aug;65(8):2081-9. doi: 10.1002/art.38020.


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 of MKX expression by interleukin-1β (IL-1β). MKX was knocked down with small interfering RNA (siRNA) to analyze the function of MKX in extracellular matrix (ECM) production and differentiation in ACL-derived cells.

Results: The expression of MKX was 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 suppressed MKX expression and reduced expression of the ligament ECM genes COL1A1 and TNXB. In contrast, SOX9, a chondrocyte master transcription factor, was up-regulated by IL-1β treatment. Importantly, knockdown of MKX expression with siRNA up-regulated SOX9 expression in ACL-derived cells, whereas the expression of COL1A1 and TNXB was 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Anterior Cruciate Ligament / metabolism*
  • Anterior Cruciate Ligament / pathology
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Chondrocytes / metabolism
  • Chondrocytes / pathology
  • Female
  • Gene Expression Regulation / physiology*
  • Gene Silencing
  • Homeodomain Proteins / physiology*
  • Humans
  • Knee Joint / metabolism*
  • Knee Joint / pathology
  • Male
  • Middle Aged
  • Osteoarthritis, Knee / metabolism*
  • Osteoarthritis, Knee / pathology
  • RNA, Small Interfering / genetics
  • SOX9 Transcription Factor / genetics
  • SOX9 Transcription Factor / metabolism
  • Transcription Factors / physiology*
  • Up-Regulation


  • Basic Helix-Loop-Helix Transcription Factors
  • Homeodomain Proteins
  • RNA, Small Interfering
  • SCX protein, human
  • SOX9 Transcription Factor
  • SOX9 protein, human
  • Transcription Factors