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A Role for Interleukin-6 in Parathyroid Hormone-Induced Bone Resorption in Vivo¹

Section of Endocrinology (A.G., M.-A.M., U.M., B.-H.S., K.I.), Yale University School of Medicine, New Haven, Connecticut 06520-8020; Laboratory of Genetics (S.R.), National Cancer Institute, Bethesda, Maryland 20892; University of Arkansas for Medical Sciences (R.J., S.M.), Little Rock, Arkansas 72205

Address all correspondence and requests for reprints to: Dr. Karl Insogna, Section of Endocrinology, Yale University School of Medicine, P.O. Box 208020, 333 Cedar Street, New Haven, Connecticut 06520-8020. E-mail: karl.insogna{at}yale.edu

Parathyroid hormone (PTH) exerts its regulatory effects on calcium homeostasis in part by stimulating the release of calcium from the skeleton. PTH stimulates bone resorption indirectly, by inducing the production by stromal/osteoblastic cells of paracrine agents which recruit and activate the bone-resorbing cell, the osteoclast. The identity of the stromal cell/osteoblast-derived paracrine factor(s) responsible for mediating the effects of PTH on osteoclasts is uncertain. Recently, it has been demonstrated that the cytokine interleukin-6 (IL-6), which potently induces osteoclastogenesis, is produced by osteoblastic cells in response to PTH. Further, we have reported that circulating levels of IL-6 are elevated in patients with primary hyperparathyroidism, and correlate with biochemical markers of bone resorption. Thus, IL-6 may play a permissive role in PTH-induced bone resorption. In the current studies, we demonstrate that low-dose PTH infusion in rodents increased serum levels of IL-6, coincident with a rise in biochemical markers of bone resorption. In mice, both acute neutralization and chronic deficiency of IL-6 were associated with markedly lower levels of biochemical markers of bone resorption in response to PTH infusion than were observed in animals with normal IL-6 production. Acute neutralization of IL-6 did not affect PTH-induced changes in markers of bone formation. These findings demonstrate that PTH regulates systemic levels of IL-6 in experimental animals, that IL-6 is an important mediator of the bone-resorbing actions of PTH in vivo and suggest that IL-6 plays a role in coupling PTH-induced bone resorption and formation.

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