P. Long et al., Tumor necrosis factor alpha-dependent proinflammatory gene induction is inhibited by cyclic tensile strain in articular chondrocytes in vitro, ARTH RHEUM, 44(10), 2001, pp. 2311-2319
Objective. To understand the intracellular mechanisms of the action of mech
anical strain on articular chondrocytes during inflammation.
Methods. One of the major mediators responsible for cartilage destruction i
n inflamed articular joints is tumor necrosis factor alpha (TNF alpha). The
refore, in this study we examined the intracellular mechanisms of actions o
f cyclic tensile strain (CTS) on the recombinant human TNF alpha (rHuTNF al
pha)-induced proinflammatory pathways in primary cultures of chondrocytes.
The expression of messenger RNA (mRNA) for TNF alpha -dependent proinflamma
tory proteins was examined by semiquantitative reverse transcriptase-polyme
rase chain reaction. The synthesis of proinflammatory proteins was examined
by Western blot analysis in cell extracts, followed by semiquantitative me
asurement of bands using densitometric analysis. Nitric oxide production wa
s measured by Griess reaction, and prostaglandin E-2 production was assesse
d by radioimmunoassays. The proteoglycan synthesis in chondrocytes was asse
ssed by incorporation of (Na2SO4)-S-35 in chondroitin sulfate proteoglycans
.
Results. By exposing chondrocytes to CTS in the presence of TNF alpha in vi
tro, we showed that CTS is an effective antagonist of TNF alpha actions and
acts as both an antiinflammatory signal and a reparative signal. CTS of lo
w magnitude suppresses TNF alpha -induced mRNA expression of multiple proin
flammatory proteins involved in catabolic responses, such as inducible nitr
ic oxide synthase, cyclooxygenase 2, and collagenase. CTS also counteracts
cartilage degradation by augmenting induction of tissue inhibitor of metall
oproteinase 2. Additionally, CTS augments the reparative process via abroga
tion of TNF alpha -induced suppression of proteoglycan synthesis. Nonethele
ss, CTS acts on chondrocytes in a TNF alpha -dependent manner, since exposu
re of chondrocytes to CTS alone had no effect on these parameters.
Conclusion. CTS of low magnitude acts as an effective antagonist of TNF alp
ha not only by inhibiting the TNF alpha -dependent induction of proinflamma
tory proteins upstream of mRNA transcription, but also by augmenting the pr
oteoglycan synthesis that is inhibited by TNF alpha.