Kostenuik P J, Harris J, Halloran B P, Turner R T, Morey-Holton E R, Bikle D D
Department of Medicine, University of California and Veterans Affairs Medical Center, San Francisco, California, USA; Department of Orthopedic Surgery, Boston University Medical Center, Boston Massachusetts, USA.
J Bone Miner Res. 1999 Jan;14(1):21-31. doi: 10.1359/jbmr.1999.14.1.21.
Skeletal unloading decreases bone formation and osteoblast number in vivo and decreases the number and proliferation of bone marrow osteoprogenitor (BMOp) 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 microg/100 g of body weight), or with vehicle via osmotic minipumps during 7 days of normal weight bearing or hind limb unloading. Marrow cells were flushed from the femur and cultured at the same initial density for up to 21 days. PTH treatment of normally loaded rats caused a 2.5-fold increase in the number of BMOp cells, with similar increases in alkaline phosphatase (ALP) activity and mineralization, compared with cultures from vehicle-treated rats. PTH treatment of hind limb unloaded rats failed to stimulate BMOp cell number, ALP activity, or mineralization. Hind limb unloading had no significant effect on PTH receptor mRNA or protein levels in the tibia. Direct in vitro PTH challenge of BMOp cells isolated from normally loaded bone failed to stimulate their proliferation and inhibited their differentiation, suggesting that the in vivo anabolic effect of intermittent PTH on BMOp cells was mediated indirectly by a PTH-induced 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 unloaded bone are resistant to the anabolic effect of intermittent PTH therapy due to their resistance to IGF-I.
骨骼失用在体内会减少骨形成和成骨细胞数量，在体外会减少骨髓骨祖细胞（BMOp）的数量和增殖。我们通过用间歇性甲状旁腺激素（PTH）（1-34）（每天1小时，剂量为8微克/100克体重）或在正常负重或后肢失用7天期间通过渗透微型泵给予赋形剂处理Sprague Dawley大鼠（n = 32），来测试PTH在体内刺激BMOp细胞的能力。从股骨中冲洗出骨髓细胞，并以相同的初始密度培养长达21天。与赋形剂处理大鼠的培养物相比，对正常负重大鼠进行PTH处理导致BMOp细胞数量增加2.5倍，碱性磷酸酶（ALP）活性和矿化也有类似增加。对后肢失用大鼠进行PTH处理未能刺激BMOp细胞数量、ALP活性或矿化。后肢失用对胫骨中PTH受体mRNA或蛋白水平没有显著影响。对从正常负重骨骼中分离的BMOp细胞进行直接体外PTH刺激未能刺激其增殖并抑制其分化，这表明间歇性PTH对BMOp细胞的体内合成代谢作用是由PTH诱导的因子间接介导的。我们假设这个因子是胰岛素样生长因子-I（IGF-I），它刺激从正常负重骨骼中分离的BMOp细胞的体外增殖和分化，但不刺激从失用骨骼中分离的BMOp细胞。这些结果表明，IGF-I介导PTH在正常负重骨骼中刺激BMOp细胞增殖的能力，并且失用骨骼中的BMOp细胞由于对IGF-I有抗性，所以对间歇性PTH治疗的合成代谢作用有抗性。
