TSG-6 - a double-edged sword for osteoarthritis (OA)

Osteoarthritis Cartilage. 2018 Feb;26(2):245-254. doi: 10.1016/j.joca.2017.10.019. Epub 2017 Nov 9.


Purpose: To explore mechanisms underlying the association of TSG-6 with osteoarthritis (OA) progression.

Methods: TSG-6-mediated heavy chain (HC) transfer (TSG-6 activity) and its association with inflammatory mediators were quantified in knee OA (n=25) synovial fluids (SFs). Paired intact and damaged cartilages from the same individuals (20 tibial and 12 meniscal) were analyzed by qRT-PCR and immunohistochemistry (IHC) for gene and protein expression of TSG-6 and components of Inter-alpha-Inhibitor (IαI) and TSG-6 activity ± spiked in IαI. Primary chondrocyte cultures (n=5) ± IL1β or TNFα were evaluated for gene expression. The effects of TSG-6 activity on cartilage extracellular matrix (ECM) assembly were explored using quantitative hyaluronan (HA)-aggrecan binding assays.

Results: TSG-6 activity was significantly associated (R > 0.683, P < 0.0002) with inflammatory mediators including TIMP-1, A2M, MMP3, VEGF, VCAM-1, ICAM-1 and IL-6. Although TSG-6 protein and mRNA were highly expressed in damaged articular and meniscal cartilage and cytokine-treated chondrocytes, there was little or no cartilage expression of components of the IαI complex (containing HC1). By IHC, TSG-6 was present throughout lesioned cartilage but HC1 only at lesioned surfaces. TSG-6 impaired HA-aggrecan assembly, but TSG-6 mediated HA-HC formation reduced this negative effect.

Conclusions: TSG-6 activity is a global inflammatory biomarker in knee OA SF. IαI, supplied from outside cartilage, only penetrates the cartilage surface, restricting TSG-6 activity (HC transfer) to this region. Therefore, unopposed TSG-6 in intermediate and deep regions of OA cartilage could possibly block matrix assembly, leading to futile synthesis and account for increased risk of OA progression.

Keywords: Biomarker; Cartilage matrix; Hyaluronan; Inflammation; Osteoarthritis progression; TSG-6.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aged
  • Biomarkers / metabolism
  • Cartilage, Articular / metabolism
  • Cell Adhesion Molecules / genetics
  • Cell Adhesion Molecules / metabolism*
  • Cells, Cultured
  • Chondrocytes / metabolism
  • Female
  • Gene Expression Regulation
  • Humans
  • Inflammation Mediators / metabolism
  • Male
  • Middle Aged
  • Osteoarthritis, Knee / genetics
  • Osteoarthritis, Knee / metabolism*
  • RNA, Messenger / genetics
  • Synovial Fluid / metabolism


  • Biomarkers
  • Cell Adhesion Molecules
  • Inflammation Mediators
  • RNA, Messenger
  • TNFAIP6 protein, human