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OP0026 in vivo inhibition of endogenous tgf-beta activity reduces osteophyte size and cartilage proteoglycan content
  1. A Scharstuhl,
  2. P Van der Kraan,
  3. E Vitters,
  4. H Van Beuningen,
  5. W Van der Berg
  1. Department of Rheumatology, University Medical Centre Nijmegen, Nijmegen, The Netherlands


Background Transforming Growth Factor-beta (TGF-beta) is considered to be a beneficial factor during cartilage repair. However, TGF-beta can also induce fibrosis and osteophytes. TGF-beta signalling starts with the binding of TGF-beta to the type II receptor, a constitutively active serine/threonine kinase. This complex then binds the type I receptor, which is subsequently phosphorylated by the type II receptor. This results in phosphorylation of downstream mediators by the type I receptor. Since the binding of TGF-beta to the extracellular domain of the type II receptor is one of high affinity, the soluble TGF-beta type II receptor, lacking cytoplasmic and membrane domains, was used as a TGF-beta antagonist.

Objectives The objective of this study was to determine the effect of inhibition of endogenous TGF-beta during an experimental model of cartilage damage.

Methods For the production of recombinant solRII, the methylotropic yeast Pichia pastoris was used. Intra-articular injection of papaine was used as a model for experimental cartilage damage and osteophyte formation. The effect of systemic delivery of solRII on endogenous TGF-beta was investigated in this model. Therefore, Alzet osmotic pumps containing either 10 mg of solRII or pumps containing solvent were implanted i.p. in C57Bl/6 mice. One day later, a 1.2% papaine solution was injected in the right knee joint. Knees were dissected on day 7 and processed for routine histology.

Results Injection of papaine into murine knee joints resulted in the formation of osteophytes and a decrease in proteoglycan (PG) content of non-calcified articular cartilage. Blocking of endogenous TGF-beta via systemic administration of solRII resulted in a reduction of 75% in osteophyte size compared to controls. Moreover, cartilage PG content was significantly decreased in solRII treated animals compared to control animals.

Conclusion This study shows for the first time that inhibition of endogenous TGF-beta leads to a reduction in osteophyte size in the papaine model of cartilage damage and osteophyte formation. This finding implicates a direct role for TGF-beta in the formation of osteophytes, a major characteristic of osteoarthritis. Furthermore, an important role for TGF-beta in the regulation of cartilage PG content is suggested, because systemic solRII treatment resulted in a decreased PG content in the papaine model. In conclusion, TGF-beta seems essential in osteophyte formation and protects against cartilage damage.

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