Skeletal unloading causes resistance of osteoprogenitor cells to parathyroid hormone and to insulin-like growth factor-I

Skeletal unloading decreases bone formation and osteoblast number in vivo a nd decreases the number and proliferation of bone marrow osteoprogenitor (B MOp) cells in vitro, We tested the ability of parathyroid hormone (PTH) to stimulate BMOp cells in vivo by treating Sprague Dawley rats (n = 32) with intermittent PTH(1-34) (1 h/day at 8 mu g/100 g of body weight), or with ve hicle via osmotic minipumps during 7 days of normal weight bearing or hind limb unloading, Marrow cells were pushed from the femur and cultured at the same initial density for up to 21 days, PTH treatment of normally loaded r ats caused a 2.5-fold increase in the number of BMOp cells, with similar in creases in alkaline phosphatase (ALP) activity and mineralization, compared ,vith cultures from vehicle-treated rats, PTH treatment of hind limb unload ed rats failed to stimulate BMOp cell number, ALP activity, or mineralizati on. Hind limb unloading had no significant effect on PTH receptor mRNA or p rotein levels in the tibia. Direct in vitro PTH challenge of BMOp cells iso lated from normally loaded bone failed to stimulate their proliferation and inhibited their differentiation, suggesting that the in vivo anabolic effe ct of intermittent PTH on BMOp cells was mediated indirectly by a PTH-induc ed factor, We hypothesize that this factor is insulin-like growth factor-I (IGF-I), which stimulated the in vitro proliferation and differentiation of BMOp cells isolated from normally loaded bone, but not from unloaded bone, These results suggest that IGF-I mediates the ability of PTH to stimulate BMOp cell proliferation in normally loaded bone, and that BMOp cells in unl oaded bone are resistant to the anabolic effect of intermittent PTH therapy due to their resistance to IGF-I.