Loss of Bone Mass and Bone Strength in Mouse Models of Hypertension: Role of Inflammation

Abstract

Approximately 1/3rd post-menopausal women and 1/5th elderly men will experience a low-energy, osteoporotic fracture. Fractures greatly impair quality of life and lower life expectancy. Though fractures have a high occurrence and economic burden, it is challenging to identify patients who are likely to experience a fragility fracture, especially those without very low bone mass. Hypertension and osteoporosis are common age-related diseases. Clinical studies show that hypertensive patients have lower bone mass, exhibit increased bone loss over time, and are at a higher risk for fragility fractures than normotensive patients. I found that bone remodeling biomarkers like osteoprotegerin, sclerostin, and tartrate-resistant acid phosphatase are highly, positively correlated with systolic blood pressure using UK Biobank data. Thus, I investigated how hypertension dysregulates bone remodeling, contributing to secondary osteoporosis and fracture risk. To define a molecular mechanism by which hypertension favors bone resorption and weaker bone, I characterized changes in the bone and marrow using two murine models of hypertension. I identified that hypertensive bone marrow has increased populations of IL17A-producing T cells which promote osteoclast formation and activation. Concurrently, hypertensive bone marrow has increased myeloid populations, including bone resorbing cells. Immunoclearing IL17A or inhibiting colony stimulating factor 1 (CSF1) receptor blunted hypertension-induced bone loss and fragility. Together, hypertension weakens bone by promoting myeloid cell production, T cell activation, and osteoclast formation. Using both in vitro and in vivo models of hypertension, I further identified the bone marrow endothelium as a source for CSF1 which supports mononuclear phagocytic cell survival, proliferation, and differentiation. This mechanism is driven by the loss of nitric oxide which is common to age-related diseases like hypertension and menopause. Estrogen loss is a leading cause of low bone mass and high fracture risk. The risk of hypertension also increases after menopause. However, it is unknown if hypertension and estrogen loss work together to decrease bone mass. Therefore, I established a preclinical model to understand how estrogen-deficiency and hypertension contribute to bone fragility and showed that hypertension markedly worsened bone loss in older ovariectomized mice.