The effects of hyaluronan on matrix metalloproteinase-3 (MMP-3), interleukin-1beta(IL-1beta), and tissue inhibitor of metalloproteinase-1 (TIMP-1) gene expression during the development of osteoarthritis

Osteoarthritis Cartilage. 1999 Mar;7(2):182-90. doi: 10.1053/joca.1998.0207.


Objective: To assess the influence of intra-articular injection of hyaluronan (HA) on expression of matrix metalloproteinase-3 (MMP-3), interleukin-1beta(IL-1beta), and tissue inhibitor of metalloproteinase-1 (TIMP-1) in cartilage and synovium during the process of osteoarthritis (OA).

Design: Eighteen mature New Zealand white rabbits underwent unilateral anterior cruciate ligament transection (ACLT) and were divided into two groups. The first group (HA injection group) received 0.3 ml of intra-articular HA injections into the ACLT knees 4 weeks after transection, once a week for 5 weeks as per clinical treatment presently utilized. The animals in the second group (no injection group) were not injected after ACLT. At death, 9 weeks following surgery, synovium and cartilage were harvested and total RNA was extracted. Gene expressions of MMP-3, IL-1beta and TIMP-1 were analyzed using reverse transcription-polymerase chain reaction (RT-PCR) for each subgroup created according to morphological grade of OA.

Results: The extent and grade of cartilage damage in the HA injection group was less severe than in the no injection group. In synovium, expression of MMP-3 and IL-1beta mRNA was suppressed in the mild grades of OA in the HA injection group. HA treatment had either no effect on MMP-3 expression in cartilage at all grades of OA or on enhanced MMP-3 and IL-1beta expression in synovium at a progressed grade. No effect of HA treatment on TIMP-1 expression was observed in either cartilage or synovium.

Conclusions: These results suggest that one of the mechanism of therapeutic effect of HA is down-regulation of MMP-3 and IL-1beta in synovium during early development of OA.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Anterior Cruciate Ligament / drug effects
  • Anterior Cruciate Ligament / metabolism
  • Down-Regulation / drug effects*
  • Hyaluronic Acid / pharmacology*
  • Interleukin-1 / biosynthesis*
  • Interleukin-1 / genetics
  • Matrix Metalloproteinase 3 / biosynthesis
  • Matrix Metalloproteinase 3 / drug effects*
  • Matrix Metalloproteinase 3 / genetics
  • Osteoarthritis, Knee / metabolism*
  • Osteoarthritis, Knee / pathology
  • RNA, Messenger / genetics
  • Rabbits
  • Reverse Transcriptase Polymerase Chain Reaction
  • Synovial Membrane / metabolism
  • Tissue Inhibitor of Metalloproteinase-1 / biosynthesis
  • Tissue Inhibitor of Metalloproteinase-1 / drug effects*
  • Tissue Inhibitor of Metalloproteinase-1 / genetics


  • Interleukin-1
  • RNA, Messenger
  • Tissue Inhibitor of Metalloproteinase-1
  • Hyaluronic Acid
  • Matrix Metalloproteinase 3