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Contenuto archiviato il 2024-05-29

Dendritic cells as possible determinants for bone marrow restricted t cells activation and bone loss in Estrogen depleted mice


Postmenopausal osteoporosis is a debilitating disease driven by estrogen deficiency. Bone loss is driven by an interplay of cytokines IL-7, TNFa, IL-1, IL-6, RANKL and IFNg. Activated, TNFa-producing T cells are critical for the increased osteoclast formation. The mechanism by which estrogen deficiency activate T cells is poorly understood.

A major breakthrough was recently made by the finding that an autoimmune-like response is central to the maintenance of osteoclastogenic cytokine secretion by T cells, including TNFa. Preliminary data have revealed that bone marrow dendritic cells, but not spleen dendritic cells, are dramatically activated by estrogen deficiency. Hypothesis: dendritic cells resident in the bone marrow may undergo a site-specific activation in estrogen deficiency and, in turn, lead to an enrichment of activated T cells.

Aim 1: To investigate in vivo the role of increased antigen presentation by dendritic cells in ovariectomy induced bone loss in mice. Strategy: OT-II transgenic mice bearing impaired T cell receptor are responsive only to the foreign antigen Ovalbumin and do not lose bone after ovariectomy. These mice will be injected with dendritic cells pulsed in vitro with Ovalbumin prior to ovariectomy. Physical analysis of bones and markers of T cells and dendritic cells activation will be evaluated.

Aim 2: To investigate the role of chemokines as possible determinants of the site-specific activation of dendritic cells. Strategy: systematic evaluation of the profile of expression of some key chemokines and their receptors on T cells and dendritic cells will be performed in controls and ovariectomized mice. Subsequently, immunostaining on human specimens for dendritic cells and chemokines will translate findings on human model. OSTEODEN will allow a substantial transfer of knowledge in the emerging field of 'Osteoimmunology', will establish long-term collaborations and will strengthen skills and independence of the proposer.

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