Graded doses of recombinant interleukin-1beta induce generalized osteopenia in rats without altering skeletal growth and joint integrity

Abstract

Background: Whereas a primary role of interleukin-1beta (IL-1beta) in local bone remodelling and articular inflammation has been well established, the effect of prolonged systemic administration of this cytokine on total skeletal Ca, somatic growth and joint tissue has not yet been investigated.

Methods: Five groups of 14 rats each, aged 7-8 weeks, had miniosmotic pumps (Alzet 200 microl) implanted and primed to release 100, 200, 500, 1,000 and 2,000 ng/kg/24 h of human recombinant IL-1beta (rIL-1beta) daily for 14 days. On days 0 and 14 total skeletal mineral content (BMC) was assessed by means of X-ray absorptiometry and vertebral and tibial growth was measured by computer-assisted radiometry. On the same days, blood was drawn and analyzed for rat growth hormone (rGH), insulin-like growth factor (IGF-1), and osteocalcin. Also 24-hour urine was collected for d-pyridinoline (dpd) determinations. Hind- and forepaw diameter as a parameter of joint inflammation was assessed using a micrometric calliper. Subsequently the animals were sacrificed and one tibia dissected for measurement of trabecular volume by computerized histomorphometry.

Results: BMC decreased in a dose-dependent manner reaching significance at 1,000 and 2,000 ng/kg (p < 0.03 and 0.04) in close correlation with tibial trabecular volumes (r = 0.84; p < 0.02). Normal vertebral and tibial growth was recorded at all dosages. There was no evidence of joint involvement. Blood rGH and IGF-1 remained normal as did osteocalcin, the latter reflecting lack of osteoblast activation. In contrast dpd increased in a dose-dependent manner indicating enhanced bone matrix turnover.

Conclusion: It is concluded that graded infusions of supraphysiological doses of rIL-1beta capable of inducing osteopenia did not affect skeletal growth in the absence of articular reaction. This is in contrast with the experience recorded in experimental arthritis in which growth retardation, in addition to osteopenia, may be caused by factors other than circulating IL-1beta.