Iwaniec U T, Wronski T J, Amblard D, Nishimura Y, van der Meulen M C H, Wade C E, Bourgeois M A, Damsky C D, Globus R K
Dept. of Physiological Sciences, Box 100144, JHMHC, Univ. of Florida, Gainesville, FL 32610, USA.
J Appl Physiol (1985). 2005 Feb;98(2):690-6. doi: 10.1152/japplphysiol.00689.2004. Epub 2004 Oct 1.
The study was designed to determine whether beta1-integrin plays a role in mediating the acute skeletal response to mechanical unloading. Transgenic (TG) mice were generated to express a dominant negative form of beta1-integrin under the control of the osteocalcin promoter, which targets expression of the transgene to mature osteoblasts. At 63 days of age, wild-type (WT) and TG mice were subjected to hindlimb unloading by tail suspension for 1 wk. Pair-fed, normally loaded WT and TG mice served as age-matched controls. Bone samples from each mouse were processed for quantitative bone histomorphometry and biomechanical testing. The skeletal phenotype of TG mice was characterized by lower cancellous bone mass in the distal femoral metaphysis (-52%) and lumbar vertebral body (-20%), reduced curvature of the proximal tibia (-20%), and decreased bone strength (-20%) and stiffness (-23%) of the femoral diaphysis with relatively normal indexes of cancellous bone turnover. Hindlimb unloading for only 1 wk induced a 10% decline in tibial curvature and a 30% loss of cancellous bone in the distal femur due to a combination of increased bone resorption and decreased bone formation in both WT and TG mice. However, the strength and stiffness of the femoral diaphysis were unaffected by short-term hindlimb unloading in both genotypes. The observed increase in osteoclast surface was greater in unloaded TG mice (92%) than in unloaded WT mice (52%). Cancellous bone formation rate was decreased in unloaded WT (-29%) and TG (-15%) mice, but, in contrast to osteoclast surface, the genotype by loading interaction was not statistically significant. The results indicate that altered integrin function in mature osteoblasts may enhance the osteoclastic response to mechanical unloading but that it does not have a major effect on the development of cancellous osteopenia in mice during the early stages of hindlimb unloading.
本研究旨在确定β1整合素在介导机械卸载引起的急性骨骼反应中是否发挥作用。构建了转基因（TG）小鼠，使其在骨钙素启动子的控制下表达β1整合素的显性负性形式，该启动子将转基因的表达靶向成熟成骨细胞。63日龄时，将野生型（WT）和TG小鼠通过尾部悬吊进行后肢卸载1周。成对喂养、正常负重的WT和TG小鼠作为年龄匹配的对照。对每只小鼠的骨样本进行定量骨组织形态计量学和生物力学测试。TG小鼠的骨骼表型特征为股骨远端干骺端松质骨量降低（-52%）、腰椎椎体松质骨量降低（-20%）、胫骨近端曲率降低（-20%）、股骨干骨强度降低（-20%）和刚度降低（-23%），而松质骨转换指标相对正常。仅1周的后肢卸载导致WT和TG小鼠胫骨曲率下降10%，股骨远端松质骨丢失30%，这是由于骨吸收增加和骨形成减少共同作用所致。然而，两种基因型的股骨干强度和刚度均不受短期后肢卸载的影响。卸载的TG小鼠中观察到的破骨细胞表面增加（92%）比卸载的WT小鼠（52%）更大。卸载的WT小鼠（-29%）和TG小鼠（-15%）的松质骨形成率均降低，但与破骨细胞表面不同，加载与基因型的相互作用无统计学意义。结果表明，成熟成骨细胞中整合素功能的改变可能增强破骨细胞对机械卸载的反应，但在小鼠后肢卸载早期，它对松质骨减少症的发展没有重大影响。
