Impacts of SARS-CoV-2 Infection and Age on Musculoskeletal Health

PROJECT SUMMARY/ABSTRACT The Coronavirus Disease 2019 (COVID-19) pandemic as of June 14, 2021, has totaled 176.02 million cases, 3.80 million deaths, and 2.37 billion vaccine doses have been administered globally. However, many have suffered prior to the vaccine and have survived or will still suffer without the vaccine. Therefore, determining the possible long-term health ramifications post-infection, how they vary based on age at the time of infection, and whether disease severity differentially impacts long-term health is imperative. Information on how COVID-19 affects bone metabolism and homeostasis is limited. This is of crucial concern because the aging population generally has higher bone loss and are at the highest risk of developing severe COVID-19 infection. The objective of the current application is to determine whether long-term deficits in bone mass are experienced following SARS-CoV-2 infection. The long-term goal is to develop potential treatment strategies to combat COVID-19 related bone loss. Preliminary studies showed that in a K18-hACE2 mouse model of COVID-19, surviving mice infected with 1x103 or 1x104 PFU exhibited up to a 24% reduction in trabecular bone volume fraction just 2 weeks post infection (p<0.001). Infected mice had a 63% increase in osteoclast numbers (p<0.0002) and a 30% increase in surface occupied by osteoclasts (p<0.02) compared to non-infected controls. Additionally, mice infected with any dose of SARS-CoV-2 had a 40% increase in megakaryocytes (MKs) within their femoral bone marrow compared to that observed in mock-infected controls (p<0.008). Further, previously conducted studies showed that MKs regulate bone mass and osteoclast (OC) formation (aged MKs increase OCs and have increased RANKL expression). Moreover, patients with severe forms of COVID-19 have upregulated expression of numerous cytokines and growth factors which is known as an inflammatory cytokine storm. Many of these cytokines, including IL-6 and TNF-α, are known to regulate OCs and/or MKs and may be responsible for the bone loss observed in the preliminary studies. Based on these observations it is hypothesized that i) SARS-CoV-2 infection results in long-term health complications in the musculoskeletal system, and ii) SARS-CoV-2 infection and the associated cytokine storm increases MK- stimulated OC formation. To test this hypothesis, two specific aims will be pursued: 1- determine whether following SARS-CoV-2 infection the bone loss observed remains over time and whether age at the time of infection impacts the severity of bone loss induced by SARS-CoV-2 infection, and: 2- investigate the mechanisms by which OC formation and bone resorption are increased as a consequence of SARS-CoV-2 infection and age, including the extent to which MKs from infected mice induce OC formation and bone resorption. The successful completion of these studies will deepen the understanding of the health implications post-infection with SARS-COV-2 and will demonstrate how disease severity, age, and MKs influence skeletal homeostasis as well as OC formation and resorption.