A role for interleukin-6 in parathyroid hormone-induced bone resorption invivo

Parathyroid hormone (PTH) exerts its regulatory effects on calcium homeosta sis in part by stimulating the release of calcium from the skeleton. PTH st imulates 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 o n osteoclasts is uncertain. Recently, it has been demonstrated that the cyt okine interleukin-g (IL-6), which potently induces osteoclastogenesis, is p roduced by osteoblastic cells in response to PTH. Further, we have reported that circulating levels of IL-6 are elevated in patients with primary hype rparathyroidism, 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 i ncreased serum levels of IL-6, coincident with a rise in biochemical marker s of bone resorption. In mice, both acute neutralization and chronic defici ency of IL-6 were associated with markedly lower levels of biochemical mark ers of bone resorption in response to PTH infusion than were observed in an imals with normal IL-6 production. Acute neutralization of IL-6 did not aff ect PTH-induced changes in markers of bone formation. These findings demons trate that PTH regulates systemic levels of IL-6 in experimental animals, t hat IL-6 is an important mediator of the bone-resorbing actions of PTH in v ivo and suggest that IL-6 plays a role in coupling PTH-induced bone resorpt ion and formation.