OSTEOBLASTS MEDIATE INSULIN-LIKE GROWTH-FACTOR-I AND GROWTH-FACTOR-II STIMULATION OF OSTEOCLAST FORMATION AND FUNCTION
OSTEOBLASTS MEDIATE INSULIN-LIKE GROWTH-FACTOR-I AND GROWTH-FACTOR-II STIMULATION OF OSTEOCLAST FORMATION AND FUNCTION
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DOI：
10.1210/en.136.1.124
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发表时间：
1995-01-01
期刊：
影响因子：
4.8
通讯作者：
MEIKLE, MC
中科院分区：
文献类型：
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作者：
HILL, PA;REYNOLDS, JJ;MEIKLE, MC
胰岛素样生长因子-I（IGF-I）和IGF-II对成骨细胞具有强大的、明确的作用，刺激其增殖并诱导胶原合成，但IGF-I和IGF-II在调节破骨细胞分化和活性中的作用仍不清楚。我们首先通过评估新生小鼠颅骨中Ca-45（2+）的释放来研究IGF-I和IGF-II的骨吸收作用。两种IGFs剂量依赖性地刺激骨吸收，IGF-I的EC（50）为8 × 10（-9）M，IGF-II为2 × 10（-8）M。然后，我们测试了IGFs对大鼠破骨细胞在象牙片上培养的骨吸收的影响。IGF-I和IGF-II均不刺激孤立的破骨细胞活性。然而，在原代小鼠成骨细胞或人骨肉瘤MG 63细胞存在下，两种IGF均增强破骨细胞的再吸收活性，IGF-I的EC（50）为5 × 10（-10）M，IGF-II的EC（50）为10（-9）M。刺激不由非成骨细胞系BALB/c/3 T3细胞介导。IGF的作用被α IR-3（一种针对I型IGF受体的抗体）阻断，但不被β-半乳糖苷酶（一种与IGF-II竞争II型IGF受体的溶酶体酶）阻断。然后，我们研究了胰岛素样生长因子对小鼠骨髓培养物中破骨细胞样多核细胞（MNCs）形成的影响。IGF-I和IGF-II剂量依赖性地增加了抗酒石酸酸性磷酸酶（TRAP）阳性MNC的数量，尽管它们的作用小于1，25-二羟维生素D-3（一种诱导破骨细胞分化的激素）。没有TRAP阳性的MNCs出现在这些激素的情况下。与真正的破骨细胞一样，TRAP阳性MNCs形成于IGF-I和IGF-II结合的[I-125]鲑鱼降钙素。当小鼠骨髓细胞培养在象牙片在IGF-I或IGF-II的存在下10天，许多吸收陷窝形成。β-半乳糖苷酶对IGF介导的破骨细胞形成没有影响。这些结果是IGF-I和IGF-II通过增强破骨细胞的形成和功能在体外刺激骨吸收的有力证据。我们的数据还表明，IGFs通过成骨细胞的中介作用，以刺激破骨细胞的活性，I型，而不是II型，IGF受体参与其反应。我们认为IGF-I和IGF-II的局部产生可能调节成骨细胞-破骨细胞相互作用和破骨细胞形成，并在骨重建中发挥重要作用。
Insulin-like growth factor-I (IGF-I) and IGF-II have powerful, well defined effects on osteoblastic cells, stimulating their proliferation and inducing collagen synthesis, but the role of IGF-I and -II in modulating osteoclast differentiation and activity remains unclear. We first examined the bone-resorptive effects of IGF-I and IGF-II by assessing Ca-45(2+) release from neonatal mouse calvarial bones. Both IGFs dose dependently stimulated bone resorption, with an EC(50) of 8 x 10(-9) M for IGF-I and 2 x 10(-8) M for IGF-II. We then tested the effects of the IGFs on bone resorption by rat isolated osteoclasts cultured on ivory slices. Neither IGF-I nor IGF-II stimulated isolated osteoclast activity. However, in the presence of either primary mouse osteoblasts or human osteosarcoma MG 63 cells, both IGFs enhanced osteoclast resorptive activity, with an EC(50) of 5 x 10(-10) M for IGF-I and 10(-9) M for IGF-II. Stimulation was not mediated by BALB/c/3T3 cells, a nonosteoblastic cell line. The effects of the IGFs were blocked by alpha IR-3, an antibody to the type I IGF receptor, but not by beta-galactosidase, a lysosomal enzyme that competes with IGF-II for the type II IGF receptor. We then examined the effects of the IGFs on the formation of osteoclast-like multinucleate cells (MNCs) in mouse bone marrow cultures. IGF-I and -II dose dependently increased the number of tartrate-resistant acid phosphatase (TRAP)-positive MNCs, although their effects were less than that of 1,25-dihydroxyvitamin D-3 (a hormone that induces osteoclast differentiation). No TRAP-positive MNCs appeared in the absence of these hormones. Like authentic osteoclasts, the TRAP-positive MNCs formed in response to IGF-I and -II bound [I-125]salmon calcitonin. When mouse bone marrow cells were cultured on ivory slices in the presence of either IGF-I or IGF-II for 10 days, numerous resorption lacunae were formed. beta-Galactosidase had no effect on IGF-mediated osteoclast formation. These results are strong evidence that both IGF-I and IGF-II stimulate bone resorption in vitro by enhancing osteoclast formation and function. Our data also suggest that the IGFs act through the intermediary of osteoblastic cells to stimulate osteoclast activity and that the type I, but not the type II, IGF receptor is involved in their responses. We propose that the local production of IGF-I and IGF-II may modulate both osteoblast-osteoclast interactions and osteoclast formation and play an important role in bone remodeling.