Examining LRP4’s Capacity to Participate in Inhibitory WNT Signaling in Bone Cells

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Medicine and Health Sciences


Context: In states of health, bone mass is sustained in a coordinated effort by osteoblasts, osteoclasts, and osteocytes. WNT signaling through low-density lipoprotein receptor related protein 5/6 (LRP5/LRP6) is one of the central signaling pathways that aids in controlling bone homeostasis. A prominent antagonist of the WNT signaling pathway is sclerostin. Low-density lipoprotein receptor related protein 4 (LRP4) is required to facilitate sclerostin-mediated inhibition of LRP5/LRP6. Clinically, mutations in LRP4 (R1170W and W1186S) which diminish its ability to bind sclerostin result in bone overgrowth. The mechanism by which LRP4 participates in this process is unknown. In vitro experiments suggest that LRP4 physically binds sclerostin and presents it directly to nearby LRP5/LRP6.

Objective: Delineating the mechanistic function(s) of LRP4 is important because if LRP4 directly provides sclerostin to LRP5/LRP6 then interfering with this process represents a potential therapeutic intervention for promoting anabolic bone formation.

Design: Genetic cloning is currently underway to fluorescently tag LPR5, LRP6, LRP4 and the LRP4 missense mutation (R1170W) for FRET/FLIM microscopy experiments. FRET/FLIM microscopy will be used to examine the live in vitro signaling dynamics of LRP4.

Results: We expect to determine if LRP4 co-localizes with LRP5 or LRP6 in living bone cells, whether this co-localization is sclerostin dependent, and whether the LRP4 missense mutation affects this interaction. Our results will characterize the novel role LRP4 plays in sclerostin-mediated WNT inhibition and capacity to effect bone mass.


Copyright 2017 all presenters

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