Introduction: Bone morphogenetic protein(BMP)-2 has been shown to be a potent enhancer of spine fusion but its role in osteoporosis has not yet been defined. The number of vertebral compression fractures related to osteoporosis is expected to double by 2025.(1) BMP-2 responsiveness has recently been shown to be enhanced by an intracellular protein, Lim Mineralization Protein(LMP)-1. Because of BMP-2’s critical role in development, attempted knockout of the BMP-2 gene is embryonically lethal. To model globally decreased BMP responsiveness, we generated an LMP knockout mouse and hypothesized it would have decreased bone mineral density.

Methods: Global Pdlim7 (mouse equivalent of LMP) knockout mice were developed using gene trapping and breeding techniques. The mice were euthanized at 18 or 26 weeks for analysis. Trabecular bone morphology of the femur and spine were measured using micro-computed tomography.

Results: The LMP KO mice weighed less and were shorter at 18 weeks, p=0.001. In the female KO mice, there was a decrease in the femur trabecular bone density (BV/TV) of 23% (p=0.06) at 18 weeks and 45% (p=0.007) at 26 weeks. This was mirrored in the vertebral body BV/TV ratio with a 25% decrease in the KOs at 26 weeks, p = 0.0005. The cortical bone volume of female KO mice was decreased by 6% (p=0.06) at 18 weeks and 8% (p=0.002) at 26 weeks. Marrow derived stromal cells from the LMP deficient mice formed significantly less mineralization.

Conclusions: We present here the development of the first LMP knockout mouse. We conclude that LMP is an important determinant of weight and length, female bone density and marrow stromal cell propensity for mineralization. We speculate that these mice will be useful in discovering and testing novel therapeutics to improve BMP-2 responsiveness and prevent vertebral fractures.

Patient Care: BMP-2 was FDA approved for anterior lumbar spinal fusions and has a humanitarian device exception for repair of symptomatic, posterolateral lumbar spine pseudoarthrosis. However, its utility has been limited by its potent cytotactic effects and resulting negative side effects. The newly developed LMP KO mouse presented here will allow for better understanding of the downstream regulators of BMP-2 across the entire organism and will likely prove to be a useful tool in studying novel therapeutics.

Learning Objectives: By the conclusion of this session, participants should be able to: 1)Describe the mechanism by which lim mineralization protien (LMP) enhances the BMP-2 pathway 2)Discuss the newly discovered phenotypes of LMP knockout mice. 3)Realize potential basic science research opportunities utilizing the LMP KO mouse model.

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