Elucidation of the osteolytic mechanism by osteoclasts
| Project/Area Number |
18590267
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
General medical chemistry
|
|---|
| Research Institution | Himeji Dokkyo University |
|---|
Principal Investigator |
TOHYAMA Yumi Himeji Dokkyo University, Faculty of Pharmaceutical Sciences, Professor (70362770)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
YAMAMURA Hirohei Kobe University, Professor Emeritus (90030882)
|
|---|
| Project Period (FY) |
2006 – 2007
|
| Project Status |
Completed (Fiscal Year 2007)
|
| Budget Amount *help |
¥3,990,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥390,000)
Fiscal Year 2007: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2006: ¥2,300,000 (Direct Cost: ¥2,300,000)
|
|---|
| Keywords | Cell / Tissue / Bio molecule / Macrophage / Osteoclast / Microtubule / Lysosome / Tyrosine kinase |
|---|
| Research Abstract |
Osteoclasts are bone-resorbing cells and play a central role in physiological bone metabolism. Osteoclasts are large multinucleated cells of hematopoietic origin and degrade the bone by releasing the acidic osteolytic granules into the isolated space on the bone matrix. However, the molecular mechanisms of osteolysis, are still unknown.
Here we show that an energy molecule ATP acts as the initiating factor of osteolytic process and promotes actin re-organization and delivery of osteolytic granules under the regulation of microtubule dynamics. From the in vitro study, we found that ATP/P2X7-mediated signaling accomplishes osteolysis by harmonizing two particular events: drastic change in the cell structure for sealing-zone formation and delivery of osteolytic granules. First, it evokes the destruction of actin-based cytoskeleton, and in turn dot-like actin-rich adhesions named podosomes are created and rearranged circularly to constitute the sealing-zone, resulting in the formation of an isolated space on the bone matrix. Second, osteolytic granules are once concentrated to the upper part of the hemispheric osteoclasts and then rapidly transported and secreted into the isolated space surrounded by sealing-zone. Furthermore, we found that acetylation/deacetylation switching of α-tubulin is essential for both sealing-zone formation and the transport of osteolytic granules, and this bidirectional kinetics of microtubules is under the control of a tyrosine kinase Syk. Our results show that ATP acts as the initiating factor of bone resorption in osteoclasts and provide evidence that a protein tyrosine kinase regulates microtubule dynamics and consequently controls the process of osteolysis including re-organization of actin structure and secretion of osteolytic granules at the downstream of nucleotide receptor (P2X7)-mediated signaling.
|
Report
(3 results)
Research Products
(20 results)
