Reference: PD 12083
The Problem
The skeleton adapts to alterations in mechanical loading by changing bone structure. Increased load results in increased bone mass as a result of increased osteoblast-mediated bone formation , whereas skeletal unloading, which occurs with immobilization, disuse, and exposure to low gravity, leads to low bone mass from increased bone resorption. The cellular targets in bone and the molecular mechanisms that sense changes in mechanical load however are uncertain. Mechanical forces (loading and unloading) are important regulators of bone mass. Disuse and/or weightlessness leads to osteoporosis while exercise and/or increase in muscle strength increases bone mass. Determining the molecular targets in bone mechanisms would be useful in defining a mechanism through which a novel therapeutic strategy can be developed to stimulate bone formation for osteoporosis disease.
The Technology Solution
Researchers at The University of Tennessee Health Science Center have discovered a bona fide mechanosensing mechanism in bone. In this regard, they found that a polycystin(Pkd1 and Pkd2)-primary cilium complex, a prototypic flow sensing mechanosensor in the kidney, is present in osteoblasts and osteocytes in bone. Most importantly, they have successfully employed in vivo mouse genetic approaches to conditionally delete Pkd1 and Kif3a from osteocytes, thereby disrupting Pkd1 signaling and primary cilia formation. These mice develop osteopenia due to defects in osteoblast-mediated bone formation. Osteoblasts and osteocytes in conditional Pkd1 and Kif3a deficient mice exhibit impaired responses to mechanical loading both in vivo and in vitro. One focus of this laboratory is skeletal response to mechanical loading and its importance in regulating bone mass. These and other findings unequivocally establish that primary cilium-polycystin complex functions as a novel mechanosensor in osteoblasts and osteocytes in bone.
This group seeks to develop therapeutic strategies to stimulate bone formation via activation of the primary cilium-polycystin complex in bone. Alternatively, they seek to develop a drug/device concept that uses a Pkd1-specific antibody conjugated to magnetic iron oxide nano-particles to activate the polycystin pathway.
Related Publication:
FASEB J. 2011 July; 25(7): 2418–2432.
Features and Benefits
• Potential treatment for osteoporosis/osteoarthritis
• Novel target for treating bone loss
Patents
U.S. Provisional Patent Application, filed March2012
U.S. Nonprovisional Patent Application, filed March 2013
The Inventor
Dr. L. Darryl Quarles is the University of Tennessee Medical Group Endowed Professor, Director of the Division of Nephrology in the Department of Medicine and Associate Dean for Research in the College of Medicine at the University of Tennessee Health Sciences Center. He has previously served as the Director of the Kidney Institute and Nephrology Division at the University of Kansas Medical Center. He is internationally recognized as an expert in the field of renal disease.