Short-term treatment of recombinant murine interleukin-4 rapidly inhibits bone formation in normal and ovariectomized mice.
Estrogen deficiency contributes to an increase in bone resorption and bone formation characterized by a high rate of bone turnover. Interleukin-4 (IL-4) is a rapid and potent inhibitor of bone resorption. We examined the short term in vivo effects of recombinant murine IL-4 (rmIL-4) on bone remodeling in normal and ovariectomized mice. Eight-week-old mice were randomized into the following five groups: (1) sham-operated mice (sham); (2) sham-operated mice infused with rmIL-4; (3) ovariectomized mice (ovx); (4) ovx infused with rmIL-4; and (5) ovx replaced by 10 or 20 microg of 17beta-estradiol (E2) for 14 or 28 days after ovariectomy, respectively. rmIL-4 at a dose of 5 microg/day was infused into ovx and sham for 3 days prior to sacrifice. Analyses were performed 14 and 28 days after operation. An increase in serum alkaline phosphatase and urinary deoxypyridinoline levels induced by ovariectomy was inhibited by the 3-day infusion of rmIL-4. In ovx, serum and urinary IL-6 levels were also increased significantly 14 days after ovariectomy, which were restored by E2 but not by rmIL-4. Histomorphometrical analysis of trabecular bone revealed that the 3-day infusion of rmIL-4 inhibited the high rate of bone turnover induced by ovariectomy, such as an increase in the osteoclastic surface (Oc.S/BS), number of osteoclasts per mm bone surface (N.Oc/BS), mineralized surface per mm bone surface (MS/BS), and bone mineral apposition rate (MAR). A significant decrease in the bone volume (BV/TV) observed in ovx was not modulated by a 3-day infusion of rmIL-4 prior to sacrifice. In sham, rmIL-4 also caused a significant decrease in the Oc.S/BS, N.Oc/BS, MS/BS, and MAR, but the BV/TV was not modulated by rmIL-4. We conclude that short term infusion of rmIL-4 in vivo rapidly inhibits not only bone resorption but also its formation in both sham-operated and ovariectomized growing mice, resulting in a low rate of bone turnover without modulating bone volume.
Okada
Y
Y
First Department of Internal Medicine, University of Occupational and Environmental Health, School of Medicine, Kitakyushu, Fukuoka, Japan.
Morimoto
I
I
Ura
K
K
Nakano
Y
Y
Tanaka
Y
Y
Nishida
S
S
Nakamura
T
T
Eto
S
S
D000469:Alkaline Phosphatase / Q000097:blood; D000596:Amino Acids / Q000652:urine; D000818:Animals; D015519:Bone Density / Q000187:drug effects; D001846:Bone Development / Q000187:drug effects*; D016723:Bone Remodeling / Q000187:drug effects*; D004797:Enzyme-Linked Immunosorbent Assay; D004958:Estradiol / Q000008:administration & dosage / Q000494:pharmacology; D005260:Female; D005269:Femur / Q000187:drug effects; D006801:Humans; D015847:Interleukin-4 / Q000494:pharmacology*; D015850:Interleukin-6 / Q000097:blood / Q000652:urine; D051379:Mice; D010010:Osteoclasts / Q000187:drug effects*; D010052:Ovariectomy; D011994:Recombinant Proteins / Q000494:pharmacology
D000596:Amino Acids; D015850:Interleukin-6; D011994:Recombinant Proteins; D015847:Interleukin-4; D004958:Estradiol; C036020:deoxypyridinoline; D000469:Alkaline Phosphatase