Serotonin-estrogen interaction in bone tissue

• Grant number: 08/09919-9
• Support Opportunities: Scholarships abroad - Research
• Start date: March 16, 2009
• End date: August 15, 2009
• Field of knowledge: Health Sciences - Dentistry
• Principal Investigator: Raquel Assed Bezerra da Silva
• Grantee: Raquel Assed Bezerra da Silva
• Host Investigator: Ricardo Bataglino
• Host Institution: Faculdade de Odontologia de Ribeirão Preto (FORP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Institution abroad: Harvard University, Cambridge, United States

Abstract

The objective of this study is to evaluate the hypothesis that estrogen modulates the bone enhancing effects of SSRIs and other serotonergic agents. This proposition will be tested in the following Specific Aims:Aim 1. To determine the effects of estrogen on the expression of components of the serotonin systemin OCs and OBs in vitro and in vivo. The effect of estrogen on the expression of the 5-HTT, VMAT1,serotonin receptors (SR), and enzymes involved in serotonin synthesis and degradation will be determined incultured OCs and OBs. Observed effects will be confirmed in vivo, in normal, ovariectomized (OVX), and OVXmice supplemented with estrogen.Aim 2. To determine the role of estrogen and serotonergic agents in the differentiation, functionalactivity, and survival of OCs and OBs. OC precursors, OB and metatarsal bones will be cultured withspecific modulators of the serotonin system based upon results from Aim 1, in the presence/absence ofestrogen. The synergistic effects of estrogen will be determined on OC (differentiation, resorptive activity andviability/apoptosis) and OB (proliferation, expression of matrix proteins, bone formation and viability/apoptosis)in vitro. Specific modulators will include fluoxetine and other SSRIs, alone and in combination with serotoninreceptor agonists, antagonists, and enzyme inhibitors as defined in expression studies. siRNA knockdown ofspecific serotonergic components will be used as a complementary strategy to pharmacologic modulators.The overall goal is to characterize the elements of the serotonin system in bone cells that synergize withestrogen to increase bone mass. Given that many FDA-approved drugs already target the serotonin system,this proof of principle studies may provide new and immediately practical approaches to the prevention and/ortreatment of human osteopenic conditions.b. Background and SignificanceNeuromediators and bone remodeling. The accepted view (AU)