PARATHYROID-HORMONE RESTORES BONE MASS AND ENHANCES OSTEOBLAST INSULIN-LIKE GROWTH-FACTOR-I GENE-EXPRESSION IN OVARIECTOMIZED RATS

In the osteopenic rat model, estrogen deficiency results in increased bone turnover with net bone loss occurring during cancellous modeling. However, estrogen-deficient rats treated with parathyroid hormone (PTH) experience a net gain of bone tissue due to the anabolic effects of PTH, To evaluate the possibility that local insulinlike growth factor I OGF-I) production modulates the in vivo balance of bone formation and resorption in ovariectomized (OVX) estrogen-deficient rats and in OVX rats treated with PTH, we have studied the expression of IGF-I mRNA in cancellous bone osteoblasts using in situ hybridization techniques. Three-month-old virgin rats were subjected to sham surgery or OVX. Two weeks later, half the OVX rats began treatment with hPTH(1-34), 5 mu g/100 g body weight, 5 days/week for 4 weeks, All animals were killed at the same time, providing three groups: sham surgery alone; OVX alone; and OVX + PTH. Bone histomorphometry performed in undecalcified sections of tibial metaphysis confirmed that OVX rats had significantly (p < 0.05) increased bone surface formation rates (BFR/BS, mu m(3)/mu m(2)/year) with osteopenia while OVX + PTH rats had increased BFWBS with increased bone volumes compared to sham animals (p < 0.05). Decalcified tissue from all three groups contained immunoreactive IGF-I, Similar tissue sections were hybridized with an S-35-labeled IGF-I antisense riboprobe. Evaluation of the specific signal over cancellous osteoblasts allowed a relative estimate of IGF-I mRNA transcript abundance in the three groups by counting silver grains per osteoblast, corrected for background activity. Despite evidence for increased BFR/BS, OVX animals had comparable frequency distributions of grain counts (after correction for background) to sham animals (88% of cells containing less than or equal to 1 grain with a mean of 0.76 +/- 0.28 grains/osteoblast vs, 81% containing less than or equal to 1 grain with a mean of 0.61 +/- 0.09, NS). However, OVX + PTH animals had over 40% of osteoblasts with greater than or equal to 2 grains per cell and twice the IGF-I mRNA abundance that either control group had (ANOVA, p < 0.001; OVX + PTH compared to either sham or OVX, p < 0.05). These data suggest that the anabolic effect of PTH is associated with increased IGF-I mRNA steady state levels; while estrogen deficiency causes increased bone turnover, increased levels of IGF-I mRNA were not observed.