Regulation of osteoclast maturation and function by resolvin E1
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Innate and adaptive immunity actively interact with bone and play an important role in bone physiology and pathology. Acute inflammation is a physiologic response that represents the hosts' first line of defense. Failure to resolve the acute inflammatory lesion leads to a chronic pathologic lesion including bone destructive conditions such as periodontitis and arthritis. Resolution of inflammation is now known to be an active process with highly coordinated interaction of cells and soluble mediators leading to the return of tissues to homeostasis, rather than a passive decay of pro-inflammatory signals as previously supposed. The ω-3 polyunsaturated fatty acid derivative resolvin E1 (RvE1) is a novel lipid mediator shown to be actively involved in the resolution of inflammation. The goal of the current studies was to determine the cellular and molecular mechanism of RvE1 impact on osteoclasts. Investigation of the actions of RvE1 treatment on the specific stages of osteoclast maturation revealed that RvE1 targeted late stages of osteoclast maturation. Observations with time-lapse vital microscopy revealed that RvE1 inhibited migration and fusion of osteoclast precursors. Migration assays confirmed that chemotactic migration of osteoclast precursors was significantly inhibited by RvE1. To determine the molecular basis of RvE1 actions, fusion proteins that mediate the migration, fusion and function of osteoclasts and the essential transcription factor NFATc1 were examined. RvE1 specifically down-regulated the pivotal osteoclast fusion protein DC-STAMP (dendritic cell specific transmembrane protein) through the receptor BLT-1. RvE1 did not impact the induction of NFATc1 nor its nuclear translocation; however, NFATc1 binding to the DC-STAMP promoter was inhibited by RvE1 treatment. The results suggest that RvE1 inhibits migration and fusion of osteoclast precursors leading to decreased numbers of mature osteoclasts. On the molecular level, RvE1 binds to the cell surface receptor BL T-1 inhibiting the downstream binding of the transcription factor NFATc1 to the fusion protein DC-STAMP promoter, leading to a reduction in the number of functioning multinucleated osteoclasts and reduced bone resorption. These observations further establish a dual role for inflammation resolution in innate immunity as well as bone preservation through the direct regulation of bone cell function.
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