Excessive osteoclast activity can lead to pathological bone resorption, which is a serious consequence of many clinical diseases including, osteoporosis, metastastic bone disease and periodontal disease. Therefore, current therapies such as bisphosphonates and denosumab (anti-RANKL antibody) have focused on inhibiting osteoclast function. Furthermore, it is becoming clear that osteoclasts are required for overall bone remodeling, and therapeutic elimination may cause more harm than good. Therefore, to improve treatment outcomes, understanding the cellular signaling networks involved in bone remodeling process is important to identifying more effective therapeutic targets. BMPs, which are currently used therapeutically to promote bone healing and regeneration, have been shown by us and others to act synergistically with RANKL, the main cytokine responsible in activating osteoclasts, to enhance osteoclastogenesis. BMPs can signal through both noncanonical MAPK signaling and canonical Smad 1/5 signaling. Previous data from our lab has shown that phospho-SMAD 1/5 expression increases in osteoclasts at the time of fusion of mononuclear precursors into multinucleated osteoclasts. I have generated mice that are conditionally deleted for Smad 1 and 5 in osteoclasts using the Cathepsin-Cre mice to test the hypothesis that Smad 1/5 expression is necessary for osteoclast fusion and activity. Secondly, I have generated preliminary data demonstrating that the expression of myosin X, an unconventional myosin responsible for regulating the sealing zone patterning in osteoclasts, increases with BMP2 stimulation of osteoclasts and is a downstream target of Smad 1/5. At the completion of my proposed experiments I expect to better understand osteoclast differentiation, particularly during osteoclast fusion and thereby uncover potential novel therapeutic targets that can be used to inhibit osteoclast function.

Public Health Relevance

Bone loss regardless of the cause is due to an increase in bone resorption by osteoclasts compared to the rate of bone formation by osteoblasts. Bone loss prevention requires an understanding of the molecular mechanisms regulating osteoclast differentiation. This application attempts to analyze one aspect of osteoclast differentiation, a key signaling pathway and its downstream target that may regulate fusion of osteoclasts from mononuclear to multinuclear cells.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32DE024679-01
Application #
8782667
Study Section
NIDCR Special Grants Review Committee (DSR)
Program Officer
Frieden, Leslie A
Project Start
2014-05-27
Project End
2016-05-26
Budget Start
2014-05-27
Budget End
2015-04-30
Support Year
1
Fiscal Year
2014
Total Cost
$68,422
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Dentistry
Type
Schools of Dentistry
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455