A PLCγ2 es a p190RhoGAP feherjek szerepenek vizsgalata az oszteoklasztok fejlodeseben es a csontanyagcsereben

• Main Author: Kertesz, Zsuzsanna
• Format: Dissertation
• Language: Hungarian
• Published: ProQuest Dissertations & Theses 01.01.2011
• Subjects: Medicine
• ISBN: 9781303009167; 1303009161

Osteoclasts are multinucleated phagocyte cells that are formed from haematopoietic stem cells. Development of mature osteoclasts is directed by M-CSF and RANKL cytokines and adhesive signals. Previous studies suggested that PLCγ2 and p190RhoGAP proteins may have a role in osteoclastogenesis which was tested by using mice genetically deficient of PLCγ2 and p190RhoGAP isoforms. During our experiments, bone marrow cells lacking PLCγ2, p190-A or p190-B were cultured under osteoclastogenic conditions and the development and resorptive function of osteoclasts was tested. We also tested the role of PLCγ2 in basal and ovariectomy-induced bone resorption by micro-CT and histomorphometric analyses of the trabecular architecture of long bone metaphyses. Postmenopausal osteoporosis was modeled by surgical ovariectomy. In vitro cultures of PLCγ2–/– bone marrow cells revealed that PLCγ2 was required for the development of multinucleated osteoclasts and for the resorption of artificial bone surface. PLCγ2 was activated upon adhesion of the cells but not by stimulation with M-CSF or RANKL in suspension. PLCγ2 was phosphorylated in a Src-family-dependent manner upon adhesion but not upon stimulation by M-CSF or RANKL. These results indicate that PLCγ2 plays a critical role in the development and function of osteoclasts and PLCγ2 likely participates in adhesion-receptor signaling. PLCγ2–/– mice had significantly higher trabecular bone mass under basal conditions than wild type mice. Surprisingly, ovariectomy-induced bone resorption in PLCγ2–/– mice was similar to, or even more robust than, that in wild type animals. Taken together, PLCγ2 is required for bone resorption under basal conditions but it does not play a major role in ovariectomy-induced bone loss. These results suggest that basal and estrogen deficiency-induced bone resorption utilizes different signaling pathways. Using bone marrow cells lacking the p190-A or the p190-B isoform of p190RhoGAPs, we were able to show that neither isoform alone is dispensable for osteoclast differentiation and function. Taken together, these results indicate that the p190-A and p190-B proteins do not have any non-redundant functions in osteoclasts.