Abstract: Series 108, Lecture 4
The Harvey Lectures Series 108 (2012—2013)
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Lecture #4: Thursday, February 21, 2013 — Watch Video of Lecture
Close to the Bone:
Novel Genes that Remodel the Skeleton
Laurie H Glimcher, MD
Stephen and Suzanne Weiss Dean
Professor of Medicine
Weill Medical College of Cornell University
New York, New York
The adult skeleton completely remodels itself every ten years. In contrast to their role in embryonic development, little is known about the genes that control post-natal skeletal remodeling. We discovered that mice lacking the adaptor protein Schnurri-3 display a profound high bone mass phenotype due to augmented anabolic bone formation. In addition to regulating bone formation by osteoblasts in a cell-intrinsic manner, Shn3 indirectly controls bone resorption in vivo. In most instances, bone formation is coupled with bone resorption, which limits the efficacy of the currentl• y marked anti-resorptives. However, in this instance, we demonstrate that these two processes can be uncoupled by genetic manipulation of Shn3 raising the possibility that its inhibition would be beneficial in the setting of diseases of low bone mass such as osteoporosis, lytic cancer metastases and erosive arthritides. We have recently used both unbiased and Schnurri-3 biased forward genetic RNAi screens coupled with extensive gene profiling analyses and small molecule screens to assemble a picture of osteoblast signaling pathways proximal to or instigated by Schnurri3. These analyses have provided novel targets in osteoblasts that control adult bone mass.
Objectives:
• Overview of frequent diseases of skeletal biology including osteoporosis.
• Basic understanding of bone formation and bone resorption processes at the cellular and molecular levels.
• Detailed understanding of how one adaptor protein, Schnurri-3, controls bone formation.
• Implications of these insights for the treatment of skeletal diseases of bone loss.