The consequences of SARS-CoV-2 infection on the musculoskeletal system represents a dangerous knowledge gap. Aging patients are at added risk for SARS-CoV-2 infection; therefore, a greater understanding of the resulting musculoskeletal sequelae of SARS-CoV-2 infection may help guide clinical strategies. This study examined fundamental bone parameters among mice treated with escalating viral loads. Male C57BL/6J (WT, n=17) and B6.Cg-Tg(K18-ACE2)2Prlmn/J mice (K18-hACE2 transgenic mice, n=21) expressing human ACE2 (TG) were divided into eight groups (n=4-6/group) and subjected to intranasal dosing of 0, 1x10 3 , 1x10 4 , and 1x10 5 PFU (plaque forming units) of human SARS-CoV-2. Animal health was assessed daily by veterinary staff using established and validated scoring criteria (activity, posture, body condition scores and body weight). We report here that mock and WT infected mice were healthy and completed the study, surviving until 12-14 days post infection (dpi). In contrast, the TG mice infected with 1x10 5 PFU all experienced severe health declines that necessitated early euthanasia (6-7 dpi). For TG mice infected with 1x10 4 PFU, 2 mice were also euthanized after 7 dpi, while 3 mice showed signs of moderate disease at day 6 dpi, but recovered fully by day 11 dpi. Four of the 5 TG mice that were infected with 1x10 3 PFU remained healthy throughout the study. This suggests that our study mimics what is seen during human disease, where some patients develop severe disease resulting in death, while others have moderate to severe disease but recover, and others are asymptomatic. At necropsy, femurs were extracted and analyzed by μCT. No difference was found in μCT determined bone parameters among the WT groups. There was, however, a significant 24.4% decrease in trabecular bone volume fraction (p=0.0009), 19.0% decrease in trabecular number (p=0.004), 6.2% decrease in trabecular thickness (p=0.04), and a 9.8% increase in trabecular separation (p=0.04) among surviving TG mice receiving any viral load compared to non-infected controls. No differences in cortical bone parameters were detected. TRAP staining revealed surviving infected mice had a significant 64% increase in osteoclast number, a 27% increase in osteoclast surface, and a 38% increase in osteoclasts per bone surface. While more studies are needed to investigate the long-term consequences of SARS-CoV-2 infection on skeletal health, this study demonstrates a significant reduction in several bone parameters and corresponding robust increases in osteoclast number observed within 2 weeks post-infection in surviving asymptomatic and moderately affected mice.
Purpose of Review Although COVID-19 was originally characterized as a respiratory disease, recent findings have shown lingering side effects in those who have recovered, and much is still unknown about the long-term consequences of the illness. Thus, the potential of unearthing multi-system dysfunction is high, with current data revealing significant impacts on musculoskeletal health. Recent Findings Multiple animal models of COVID-19 infection have revealed significant post-infection bone loss at several different skeletal sites. While how this loss occurred is unknown, this current review discusses the primary bone loss studies, and examines the possible mechanisms of action including: direct infection of bone marrow macrophages or hematopoietic progenitors, a proinflammatory response as a result of the COVID-19 induced cytokine storm, and/or a result of hypoxia and oxidative stress. This review will further examine how therapeutics used to treat COVID-19 affect the skeletal system. Finally, this review will examine the possible consequence that delayed care and limited healthcare accessibility has on musculoskeletal-related patient outcomes. Summary It is important to investigate the potential impact COVID-19 infection has on musculoskeletal health.
Type 2 diabetes (T2D) results in physiological and structural changes in bone, contributing to poor fracture healing. T2D compromises microvascular performance, which can negatively impact bone regeneration as angiogenesis is required for new bone formation. We examined the effects of bone morphogenetic protein‐2 (BMP‐2) administered locally at the time of femoral segmental bone defect (SBD) surgery, and its angiogenic impacts on endothelial cells (ECs) isolated from the ipsilateral or contralateral tibia in T2D mice. Male C57BL/6 mice were fed either a low‐fat diet (LFD) or high‐fat diet (HFD) starting at 8 weeks. After 12 weeks, the T2D phenotype in HFD mice was confirmed via glucose and insulin tolerance testing and echoMRI, and all mice underwent SBD surgery. Mice were treated with BMP‐2 (5 µg) or saline at the time of surgery. Three weeks postsurgery, bone marrow ECs were isolated from ipsilateral and contralateral tibias, and proliferation, angiogenic potential, and gene expression of the cells was analyzed. BMP‐2 treatment increased EC proliferation by two fold compared with saline in LFD contralateral tibia ECs, but no changes were seen in surgical tibia EC proliferation. BMP‐2 treatment enhanced vessel‐like structure formation in HFD mice whereas, the opposite was observed in LFD mice. Still, in BMP‐2 treated LFD mice, ipsilateral tibia ECs increased expression of CD31, FLT‐1, ANGPT1, and ANGPT2. These data suggest that the modulating effects of T2D and BMP‐2 on the microenvironment of bone marrow ECs may differentially influence angiogenic properties at the fractured limb versus the contralateral limb.
With an aging world population, there is an increased risk of fracture and impaired healing. One contributing factor may be aging‐associated decreases in vascular function; thus, enhancing angiogenesis could improve fracture healing. Both bone morphogenetic protein 2 (BMP‐2) and thrombopoietin (TPO) have pro‐angiogenic effects. The aim of this study was to investigate the effects of treatment with BMP‐2 or TPO on the in vitro angiogenic and proliferative potential of endothelial cells (ECs) isolated from lungs (LECs) or bone marrow (BMECs) of young (3‐4 months) and old (22‐24 months), male and female, C57BL/6J mice. Cell proliferation, vessel‐like structure formation, migration, and gene expression were used to evaluate angiogenic properties. In vitro characterization of ECs generally showed impaired vessel‐like structure formation and proliferation in old ECs compared to young ECs, but improved migration characteristics in old BMECs. Differential sex‐based angiogenic responses were observed, especially with respect to drug treatments and gene expression. Importantly, these studies suggest that NTN1, ROBO2, and SLIT3, along with angiogenic markers (CD31, FLT‐1, ANGPT1, and ANGP2) differentially regulate EC proliferation and functional outcomes based on treatment, sex, and age. Furthermore, treatment of old ECs with TPO typically improved vessel‐like structure parameters, but impaired migration. Thus, TPO may serve as an alternative treatment to BMP‐2 for fracture healing in aging owing to improved angiogenesis and fracture healing, and the lack of side effects associated with BMP‐2.
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