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© The Rockefeller University Press, 0021-9525/1999//183 $5.00
The Journal of Cell Biology, Volume 145, Number 1, , 1999 183-189

Integrin-regulated Secretion of Interleukin 4: A Novel Pathway of Mechanotransduction in Human Articular Chondrocytes

S.J. Millward-Sadler^*, M.O. Wright, H.-S. Lee^*,, K. Nishida^*, H. Caldwell^*, G. Nuki^||, and D.M. Salter^*

^* Department of Pathology and Department of Physiology, University of Edinburgh Medical School, Edinburgh, United Kingdom EH8 9AG; National Defense Medical Center and Tri-Service General Hospital, Taiwan 100; and ^|| Rheumatic Diseases Unit, Western General Hospital, Edinburgh, United Kingdom EH4 2XU

Chondrocyte function is regulated partly by mechanical stimulation. Optimal mechanical stimulation maintains articular cartilage integrity, whereas abnormal mechanical stimulation results in development and progression of osteoarthritis (OA). The responses of signal transduction pathways in human articular chondrocytes (HAC) to mechanical stimuli remain unclear. Previous work has shown the involvement of integrins and integrin-associated signaling pathways in activation of plasma membrane apamin-sensitive Ca²⁺-activated K⁺ channels that results in membrane hyperpolarization of HAC after 0.33 Hz cyclical mechanical stimulation. To further investigate mechanotransduction pathways in HAC and show that the hyperpolarization response to mechanical stimulation is a result of an integrin-dependent release of a transferable secreted factor, we used this response. Neutralizing antibodies to interleukin 4 (IL-4) and IL-4 receptor inhibit mechanically induced membrane hyperpolarization and anti–IL-4 antibodies neutralize the hyperpolarizing activity of medium from mechanically stimulated cells. Antibodies to interleukin 1β (IL-1β) and cytokine receptors, interleukin 1 receptor type I and the common chain/CD132 () have no effect on me- chanically induced membrane hyperpolarization. Chondrocytes from IL-4 knockout mice fail to show a membrane hyperpolarization response to cyclical mechanical stimulation. Mechanically induced release of the chondroprotective cytokine IL-4 from HAC with subsequent autocrine/paracrine activity is likely to be an important regulatory pathway in the maintenance of articular cartilage structure and function. Finally, dysfunction of this pathway may be implicated in OA.

Key Words: chondrocyte • mechanotransduction • integrin • interleukin 4 • ion channels

Abbreviations used in this paper: CM, conditioned medium; c, common gamma chain; ECM, extracellular matrix; HAC, human articular chondrocytes; IFN-, interferon gamma; IL, interleukin; IP3, inositol triphosphate; MMP, matrix metalloproteinase; OA, osteoarthritis; PIS, pressure-induced strain; PLC, phospholipase C; PKC, protein kinase C; RT-PCR, reverse transcriptase-PCR; SK, small conductance Ca²⁺-dependent K⁺ channels; TGF-β1, transforming growth factor β1; TIMP, tissue inhibitor of matrix metalloproteinase.

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