Skeletal unloading induces resistance to insulin-like growth factor I on bone formation
Skeletal unloading induces resistance to insulin-like growth factor I on bone formation
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DOI：
10.1016/s8756-3282(03)00088-7
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发表时间：
2003-06-01
期刊：
影响因子：
4.1
通讯作者：
Bikle, DD
中科院分区：
文献类型：
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作者：
Sakata, T;Halloran, BP;Bikle, DD
骨骼卸载导致与成骨细胞数量减少、骨矿化受损以及骨祖细胞增殖和分化改变相关的骨形成抑制。虽然这种变化可能是由多种因素介导的，但对胰岛素样生长因子I（IGF-I）的生长促进作用的抵抗已被假设发挥重要作用。为了确定骨骼卸载是否会诱导IGF-I对骨形成的抵抗，我们检查了卸载（后肢抬高）和正常负载的胫骨和股骨对IGF-I给药的反应。为了消除外源性IGF-I给药期间内源性生长激素产生和分泌的变量，我们使用生长激素缺乏性侏儒大鼠（dw-4）。在卸载或正常负载的7天和14天期间，给予大鼠IGF-I（2.5 mg/kg/天）或溶剂。这显著增加了正常负荷和未负荷大鼠的血清IGF-I水平。卸载不影响溶剂处理大鼠的IGF-I血清水平。IGF-I显着增加骨膜骨形成在正常负荷大鼠胫腓交界处。卸载减少了载体治疗大鼠的骨形成，并阻断了IGF-I增加骨形成的能力。另一方面，IGF-I增加了后肢抬高和正常负荷大鼠肱骨中点（在该模型中通常负荷）的骨膜骨形成。IGF-I显著增加正常负荷大鼠骨髓骨祖细胞（BMOp）的成骨集落数量、总ALP活性和总矿化。卸载降低了这些参数在溶剂处理的大鼠，并阻断了IGF-I的刺激。此外，IGF-I给药（10 ng/ml）在体外显着增加的BMOp细胞的细胞增殖分离自正常加载的骨，但不卸载骨的细胞。这些结果表明，骨骼卸载诱导抵抗IGF-I对骨形成。(C)2003 Elsevier Science（美国）。All rights reserved.
Skeletal unloading results in an inhibition of bone formation associated with a decrease in osteoblast number, impaired mineralization of bone, and altered proliferation and differentiation of osteoprogenitor cells. Although such changes are likely to be mediated by multiple factors, resistance to the growth-promoting action of insulin-like growth factor I (IGF-I) has been hypothesized to play an important role. To determine whether skeletal unloading induces resistance to IGF-I on bone formation, we examined the response of unloaded (hindlimb elevation) and normally loaded tibia and femur to IGF-I administration. To eliminate the variable of endogenous growth hormone production and secretion during exogenous IGF-I administration, we used growth hormone-deficient dwarf rats (dw-4). The rats were given IGF-I (2.5 mg/kg/day) or vehicle during 7 and 14 days of unloading or normal loading. This significantly increased the serum level of IGF-I in both the normally loaded and unloaded rats. Unloading did not affect the serum level of IGF-I in the vehicle-treated rats. IGF-I markedly increased periosteal bone formation at the tibiofibular junction of normally loaded rats. Unloading decreased bone formation in the vehicle-treated rats, and blocked the ability of IGF-I to increase bone formation. On the other hand, IGF-I increased periosteal bone formation at the midpoint of the humerus (normally loaded in this model) in both hindlimb-elevated and normally loaded rats. IGF-I significantly increased osteogenic colony number, total ALP activity, and total mineralization in bone marrow osteoprogenitor (BMOp) cells of normally loaded rats. Unloading reduced these parameters in the vehicle-treated rats, and blocked the stimulation by IGF-I. Furthermore, IGF-I administration (10 ng/ml) in vitro significantly increased cell proliferation of the BMOp cells isolated from normally loaded bone, but not that of cells from unloaded bone. These results indicate that skeletal unloading induces resistance to IGF-I on bone formation. (C) 2003 Elsevier Science (USA). All rights reserved.