Current therapeutics such as bisphosphonates or anabolic agents do not always effectively prevent or treat osteoporosis and inflammatory bone loss in rheumatoid arthritis, periodontitis, and implant loosening. Therefore, there is a barrier t developing effective therapeutics to preserve bone. During the 4-year parent grant award period (2007-2011), we made significant progress in delineating molecular pathways such as NFATc1 and pERK1/2 in the context of inflammatory osteolysis. In order to translate our findings into a preclinical arena, we screened several drug candidates and identified PTH(1-34) as a novel anti-inflammatory agent. Now, we are setting a new direction for our A1 competitive renewal proposal that seeks to unravel, an as yet unknown, anti-inflammatory function of PTH(1-34) in the context of inflammatory osteoclastogenesis and osteolysis. LPS has been implicated in bone infection and implant-related bone loss. LPS has been commonly used to establish a new therapeutic concept. When PTH(1-34) was delivered topically, we observed that PTH(1-34) surprisingly inhibited LPS-induced osteoclastogenesis in vivo. Subsequent experiments were conducted to investigate this phenomenon. We observed that PTH(1-34) was not inhibiting RANKL through osteoclast precursors, but was inhibiting pro-osteoclastogenic cytokines like MCSF in osteoblast cells. LPS induced phosphorylation of ERK1/2, a common inflammatory osteolysis signal transducer, was also inhibited via LPS treatment. We have optimized PTH(1-34) doses and delivery methods for the proposed experiments. Therefore, we developed a therapeutically innovative hypothesis that regionally administered low-dose PTH(1- 34) inhibits inflammatory bone loss by suppressing osteoclastogenic cytokine production in osteogenic lineage cells. We seek to investigate this hypothesis through two parallel Aims and ultimately, establish a novel anti- osteoclastogenic function of PTH(1-34).
In Specific Aim 1, we will establish a novel anti-inflammatory role of PTH(1-34) in the context of osteolysis in vivo. We will determine whether regionally applied low-dose PTH(1-34) in a hydrogel prevents inflammatory osteolysis in response to clinically relevant stimuli such as RANKL, LPS and hip joint simulator generated CoCr wear particles. Osteoclastogenesis will be measured by cathepsin K optical signals and by counting osteoclast numbers. Dynamic bone histomorphometry will enable us to examine bone turnover.
In Specific Aim 2, we will define the mechanism by which PTH(1-34) exhibits an anti- inflammatory effect in osteoblasts. We will examine the functional interactions between pERK/cytokine expression and two diverging PTH signaling pathways (Gs/adenylate cyclase/cAMP and Gq/11-phospholipase C). We will further delineate the functional importance of each pathway using pathway-specific analogs, our in vivo osteolysis and in vitro macrophage-osteoprogenitor co-culture models. In summary, we will provide novel therapeutic and mechanistic insights into specific anti-inflammatory function of hydrogel-based delivery of low- dose PTH in the setting of inflammatory osteolysis for drug development.

Public Health Relevance

Current therapeutics such as bisphosphonates or anabolic agents do not always effectively prevent or treat osteoporosis and inflammatory bone loss in rheumatoid arthritis, periodontitis, and implant loosening. Therefore, there is an unmet need to develop effective therapeutics that will preserve bone. This proposal will provide insights on the specific anti-inflammatory function of hydrogel-based delivery of low-dose PTH in the setting of inflammatory osteolysis for drug development.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01EB006834-07
Application #
8658428
Study Section
Musculoskeletal Tissue Engineering Study Section (MTE)
Program Officer
Hunziker, Rosemarie
Project Start
Project End
Budget Start
Budget End
Support Year
7
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Orthopedics
Type
Schools of Medicine
DUNS #
City
New York
State
NY
Country
United States
Zip Code
10032
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