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.
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.
|Patel, Neel; Nizami, Saqib; Song, Lee et al. (2015) CA-074Me compound inhibits osteoclastogenesis via suppression of the NFATc1 and c-FOS signaling pathways. J Orthop Res 33:1474-86|
|Worthley, Daniel L; Churchill, Michael; Compton, Jocelyn T et al. (2015) Gremlin 1 identifies a skeletal stem cell with bone, cartilage, and reticular stromal potential. Cell 160:269-84|
|Carrisoza-Gaytan, Rolando; Liu, Yu; Flores, Daniel et al. (2014) Effects of biomechanical forces on signaling in the cortical collecting duct (CCD). Am J Physiol Renal Physiol 307:F195-204|
|Kim, Kyung Ok; Hsu, Anny C; Lee, Heon Goo et al. (2014) Proteomic identification of 14-3-3Ïµ as a linker protein between pERK1/2 inhibition and BIM upregulation in human osteosarcoma cells. J Orthop Res 32:848-54|
|Lee, Heon Goo; Hsu, Anny; Goto, Hana et al. (2013) Aggravation of inflammatory response by costimulation with titanium particles and mechanical perturbations in osteoblast- and macrophage-like cells. Am J Physiol Cell Physiol 304:C431-9|
|Lee, Heon Goo; Minematsu, Hiroshi; Kim, Kyung Ok et al. (2011) Actin and ERK1/2-CEBPÎ² signaling mediates phagocytosis-induced innate immune response of osteoprogenitor cells. Biomaterials 32:9197-206|
|Minematsu, Hiroshi; Shin, Mike J; Celil Aydemir, Ayse B et al. (2011) Nuclear presence of nuclear factor of activated T cells (NFAT) c3 and c4 is required for Toll-like receptor-activated innate inflammatory response of monocytes/macrophages. Cell Signal 23:1785-93|
|Seo, Sung Wook; Lee, Daniel; Minematsu, Hiroshi et al. (2010) Targeting extracellular signal-regulated kinase (ERK) signaling has therapeutic implications for inflammatory osteolysis. Bone 46:695-702|
|Celil Aydemir, Ayse B; Minematsu, Hiroshi; Gardner, Thomas R et al. (2010) Nuclear factor of activated T cells mediates fluid shear stress- and tensile strain-induced Cox2 in human and murine bone cells. Bone 46:167-75|
|Suratwala, Sanjeev J; Cho, Samuel K; van Raalte, Jonathan J et al. (2008) Enhancement of periprosthetic bone quality with topical hydroxyapatite-bisphosphonate composite. J Bone Joint Surg Am 90:2189-96|
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