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Effects of disrupted ₁-integrin function on the skeletal response to short-term hindlimb unloading in mice

¹Department of Physiological Sciences, University of Florida, Gainesville, Florida; ²Life Sciences Division, National Aeronautics and Space Administration-Ames Research Center, Moffett Field, California; ³Sibley School of Mechanical and Aerospace Engineering, Cornell University, Ithaca, New York; and ⁴Department of Stomatology, University of California, San Francisco, California

Submitted 2 July 2004 ; accepted in final form 24 September 2004

The study was designed to determine whether ₁-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 ₁-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.

cancellous bone; bone formation; bone resorption; bone strength