Stress, particularly aging, manifests itself on many organ systems, including both bone homeostasis and hematopoiesis. Defects in the function of hematopoietic stem cells (HSC) with age, particularly myeloid skewing with increased incidence of myeloid malignancies and osteoporosis, and age associated changes in the HSC supportive niche are documented. It is now appreciated that alterations in HSC function can be the consequence of age-associated changes in the marrow microenvironment, however mechanisms are unknown. Drs. Pelus, Orschell and Kacena bring individual long standing expertise in regulation of steady state and stressed hematopoiesis and bone homeostasis. They have forged a new collaboration based upon the findings in the Kacena laboratory of a novel role of megakaryocytes (MKs) produced by the hematopoietic system in stimulating bone formation by osteoblasts (OBs);findings in the Pelus laboratory that define important roles for the major eicosanoid prostaglandin E2 (PGE2) in regulating HSC function and survival both intrinsic and extrinsic through OBs in the hematopoietic niche;and development in the Orschell laboratory of novel radiation models and the finding of loss of HSC function with age. The PIs hypothesize that the interaction of MKs, OBs, and PGE2 represents a static regulatory osteoimmuno triad for bone homeostasis and hematopoietic niche function, and a focus of dysfunction following stress/aging. In this proposal we seek to understand how MKs regulate OB function and the role played by PGE2. Specifically, we will determine, in aging and following radiation, whether MKs stimulate OBs to function in support of hematopoiesis at the expense of synthesizing bone matrix. This would be a paradigm shift in the understanding of primary roles for both MKs and OBs and our understanding of bone loss in aging. Our proposed studies are innovative with respect to the potential role of MKs, alone or with PGE2 (a known bone anabolic molecule), as anabolic agents to improve bone health, and understanding the normal bone and hematopoietic loss of function as a consequence of aging. This knowledge will have a significant impact to the design of improved bone health strategies. In addition, understanding how MKs and PGE2 regulate OB proliferation in the context of the static and recovering hematopoietic niche will aid development of therapeutic strategies to accelerate hematopoietic recovery following chemo/radio therapy for cancer, radiation exposure from terrorism events or accidental radiation exposure injury, and after bone marrow transplantation, and the effects of age on these parameters. Unmet medical needs still exist in each of these areas with impact measured in educed morbidity and cost.
Understanding the functions of the osteoimmuno MK/PGE2/OB triad will provide a better understanding of the role of this osteoimmuno triad in homeostasis, upon stress and aging and likely allow for the development of novel treatments to enhance recovery of hematopoiesis following injury, disease and aging, and new therapeutic strategies for osteoporosis.
|Plett, P Artur; Sampson, Carol H; Chua, Hui Lin et al. (2015) The H-ARS Dose Response Relationship (DRR): Validation and Variables. Health Phys 109:391-8|