The Effect of the LRP5 High Bone Mass Mutation under Bone Wasting Stimuli

INTRODUCTION: The low density lipoprotein receptor-related protein-5 (LRP5), a coreceptor in the Wnt signaling pathway, has been shown to be important in modulating bone mass in humans and in mice. Among humans, a loss of function mutation in LRP5 results in a severe osteoporotic disease, while certain missense mutations in the gene (gain-of-function mutations) result in a high bone mass (HBM) phenotype. Lrp5 knockout mice have been shown to have a drastically reduced to nonexistent response to mechanical signaling, thus suggesting the importance of this protein to bone mechanotransduction. However, it is currently unclear if and how the gain-of-function HBM mutation alters bone mechanotransduction. To address this issue and to explore the potential of the HBM mutation to protect the tissue from bone loss stimuli, we have inserted (knocked-in) two missense LRP5 mutations, A214V and G171V, into mice. We hypothesized that the HBM mutations would prevent bone loss under bone-wasting stimuli. The role of the HBM mutation in bone loss environments was examined using three models. First, a hindlimb-suspension model was used that suspends and unloads the hindlimbs, while allowing the forelimbs to maintain contact with the cage floor. This method has been used to model disuse-induced bone loss as seen in bedridden patients. A second approach using injections of Botulinum toxin A (Botox) in the right hindlimb musculature to paralyze and thus underload this limb was also used. This Botox model may be a better model for representing localized disuse osteoporosis, as seen in patients with muscular impairment or in stress shielding effects of hip and knee implants. Finally, an ovariectomy model was used to model menopause-associated bone loss. Overall, these experiments will allow us to determine whether the mutant receptor confers bone-protective effects in the presence of bone-wasting stimuli arising from different etiologies.