Post-Transcriptional Control of Aging-Associated Inflammation and Bone Homeostasis

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ABSTRACT With advancing age, the immune system undergoes dynamic changes characterized by both impairment of adaptive immunity and activation of low-grade chronic inflammation. This chronic activation of inflammation associated with aging or `inflammaging'. Tristetraprolin (TTP) is an RNA binding proteins that post-translationally bind to adenylate-uridylate–rich elements in the 3′-UTR of target mRNAs (including key pro-inflammatory mRNAs e.g. TNFα, COX-2 and IL-6) to promote their rapid turnover. Importantly, we have recently demonstrated that failure to regulate expression of cytokines at the posttranscriptional level contributes to chronic inflammation and spontaneous alveolar bone loss with age in TTP-/- mice compared to age/sex match controls. Thus, TTP expression appears to be essential for alveolar bone homeostasis in an age-dependent manner. Our preliminary data in this application and recently published data strongly support the concept that macrophages and myeloid- derived suppressor cell (MDSC) populations are expanded with age in TTP-/- mice, with concomitant reduction in lymphocyte populations. Taken together, our results support that notion that TTP may be a critical intrinsic factor of inflammaging and myeloid lineage expansion/differentiation that contributes towards skeletal homeostasis. We propose to test the hypothesis that TTP controls inflammaging and impacts alveolar bone and long bone skeletal health with age. The specific aims of the proposal are: 1) define the role of myeloid-derived TTP on bone homeostasis with age; 2) determine the mechanisms that TTP uses to alter osteoclastogenesis with age; and 3) Establish if increased TTP expression alters bone remodeling during healthy aging. At the conclusion of these studies, new insights regarding TTP will be provided for future studies where would be potentially a therapeutic target for healthy aging of the oral and non-oral skeletal tissues.