OP0026 in vivo inhibition of endogenous tgf-beta activity reduces osteophyte size and cartilage proteoglycan content. (1st June 2001) - Scharstuhl, A
Abstract : 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.