Bone and Connective Tissues/Tissue Engineering

KEITH KIRKWOOD DDS, PhD personal profile

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

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 protein that post-translationally bind to adenylate-uridylate–rich elements in the 3′-UTR of target mRNAs (including key pro-inflammatory mRNAs e.g. TNFa, 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. For these studies, both global and conditional and knock-in mice are used to explore bone biology and osteoimmunological changes in TTP during the aging process

Dr. Kirkwood’s Additional Research