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Adrenocorticotropin Evokes Transient Elevations in Intracellular Free Calcium ([Ca²⁺]_i) and Increases Basal [Ca²⁺]_i in Resting Chondrocytes through a Phospholipase C-Dependent Mechanism

Department of Medicine, Winthrop University Hospital (J.F.E., S.P., J.F.A., J.K.Y.), Mineola, New York 11501; Department of Pathology, Texas Tech University Health Sciences Center (C.-L.S.), Lubbock, Texas 79430; Health Sciences Center, State University of New York (J.F.A., J.K.Y.), Stony Brook, New York 11794; and Department of Decision Sciences, St. John’s University (S.P.), Jamaica, New York 11439

Address all correspondence and requests for reprints to: Dr. Jodi F. Evans, Department of Medicine, Winthrop University Hospital, 222 Station Plaza North, Suite 501, Mineola, New York 11501. E-mail: jevans{at}winthrop.org.

Both clinical and in vitro evidence points to the involvement of the melanocortin peptide, ACTH, in the terminal differentiation of chondrocytes. Terminal differentiation along the endochondral pathway is responsible for linear growth, but also plays a role in osteoarthritic cartilage degeneration. Chondrocyte terminal differentiation is associated with an incremental increase in chondrocyte basal intracellular free calcium ([Ca²⁺]_i), and ACTH agonism of melanocortin receptors is known to mobilize [Ca²⁺]_i. Using differentiated resting chondrocytes highly expressing type II collagen and aggrecan, we examined the influence of both ACTH and dexamethasone treatment on matrix gene transcription and [Ca²⁺]_i. Resting chondrocytes treated concurrently with dexamethasone and ACTH expressed matrix gene transcripts in a pattern consistent with that of rapid terminal differentiation. Using the fluorescent Ca²⁺ indicator, fura-2, we determined that ACTH evokes transient increases in [Ca²⁺]_i and elevates basal Ca²⁺ levels in resting chondrocytes. The transient increases were initiated intracellularly, were abrogated by the phospholipase C-specific inhibitor, U73122, and were partly attenuated by myo-inositol 1,4,5-triphosphate receptor inhibition via 10 mM caffeine. The initial intracellular release also resulted in store-operated calcium entry, presumably through store-operated channels. Dexamethasone priming increased both the initial ACTH-evoked [Ca²⁺]_i release and the subsequent store-operated calcium entry. These data demonstrate roles for ACTH and glucocorticoid in the regulation of chondrocyte terminal differentiation. Because the actions of ACTH are mediated through known G protein-coupled receptors, the melanocortin receptors, these data may provide a new therapeutic target in the treatment of growth deficiencies and cartilage degeneration.

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