Evaluation of the role of low-density lipoprotein receptor -related protein 5 (LRP5) in regulating bone mass

Nathaniel D Pitner, Purdue University

Abstract

Genetic studies in humans have shown loss-of-function mutations in the LRP5 gene to be responsible for osteoporosis-pseudoglioma syndrome (OPPG), an autosomal recessive disorder characterized by juvenile-onset osteoporosis and abnormal eye development. As evidenced by severely low bone mineral density and increased fracture incidence in OPPG individuals, LRP5 plays a critical role in bone mass regulation. The present studies show that Lrp5-deficient mice (Lrp5-/-) recapitulate the OPPG phenotype of low bone mass and increased bone fragility, making these mice a useful model for studying the mechanisms by which Lrp5 regulates bone development and homeostasis. Bone tissue analyses by X-ray diffraction and by inductively coupled plasma-atomic emission spectrometry did not reveal any measurable differences in crystal structure or chemical composition, respectively. Thus, it was concluded that the increased bone fragility observed in Lrp5-/- mice is a result of reduced bone mass and smaller bone geometry and is not a result of altered crystal structure or chemical composition. In vivo pDXA scans revealed site-specific osteopenia in Lrp5-/- mice, especially in load-bearing bones such as the femur and lumbar spine. This finding led to the hypothesis that Lrp5 deficiency causes a decrease in bone tissue responsiveness to mechanical loading. To test this proposal, 16-week-old Lrp5-/- and Lrp5+/+ mice were subjected to in vivo ulnar loading at three different load magnitudes, 2 Hz, 60 cycles/day for three consecutive days. The results showed that Lrp5-/- mice were significantly less responsive to mechanical loading, suggesting Lrp5 plays a role in skeletal mechanoreactivity. Intermittent dosing of parathyroid hormone (PTH) is an established anabolic stimulus in bone. To test for specificity of the effect of Lrp5-deficiency on bone tissue responsiveness, 12-week-old Lrp5-/- and Lrp5+/+ mice were subjected to a 4-week daily treatment (5 days/week) consisting of subcutaneous injections of either 40 μg/kg body mass/day of PTH(1-34) or vehicle. The results revealed no differences in PTH-responsiveness between the skeletons of Lrp5-/- and Lrp5+/+ mice, suggesting that the effect of Lrp5-deficiency on bone tissue responsiveness is specific to mechanoresponsiveness and does not involve PTH mechanisms. Future studies will further elucidate the molecular mechanisms by which Lrp5 affects bone mass accrual and proper skeletal development, aiding in the identification of potential targets for future pharmacological treatments of osteoporosis. It is my hope that the work presented here provides a framework for future studies that will further elucidate the molecular mechanisms by which Lrp5 affects accrual of bone mass and proper development of the skeleton. Identification of these pathways and the molecules involved will unveil potential targets for future pharmacological treatments of osteoporosis.

Degree

Ph.D.

Advisors

Turner, Purdue University.

Subject Area

Biomedical research

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