Ambient PM2.5 Exposure and Bone Homeostasis: Analysis of UK Biobank Data and Experimental Studies in Mice and in Vitro

Background: Previous evidence has identified exposure to fine ambient particulate matter (PM2.5) as a leading risk factor for adverse health outcomes. However, to date, only a few studies have examined the potential association between long-term exposure to PM2.5 and bone homeostasis. Objective: We sought to examine the relationship between long-term PM2.5 exposure and bone health and explore its potential mechanism. Methods: This research included both observational and experimental studies. First, based on human data from UK Biobank, linear regression was used to explore the associations between long-term exposure to PM2.5 (i.e., annual average PM2.5 concentration for 2010) and bone mineral density [BMD; i.e., heel BMD (n=37,440) and femur neck and lumbar spine BMD (n=29,766)], which were measured during 2014–2020. For the experimental animal study, C57BL/6 male mice were assigned to ambient PM2.5 or filtered air for 6 months via a whole-body exposure system. Micro-computed tomography analyses were applied to measure BMD and bone microstructures. Biomarkers for bone turnover and inflammation were examined with histological staining, immunohistochemistry staining, and enzyme-linked immunosorbent assay. We also performed tartrate-resistant acid phosphatase (TRAP) staining and bone resorption assay to determine the effect of PM2.5 exposure on osteoclast activity in vitro. In addition, the potential downstream regulators were assessed by real-time polymerase chain reaction and western blot. Results: We observed that long-term exposure to PM2.5 was significantly associated with lower BMD at different anatomical sites, according to the analysis of UK Biobank data. In experimental study, mice exposed long-term to PM2.5 exhibited excessive osteoclastogenesis, dysregulated osteogenesis, higher tumor necrosis factor-alpha (TNF-α) expression, and shorter femur length than control mice, but they demonstrated no significant differences in femur structure or BMD. In vitro, cells stimulated with conditional medium of PM2.5-stimulated macrophages had aberrant osteoclastogenesis and differences in the protein/mRNA expression of members of the TNF-α/Traf6/c-Fos pathway, which could be partially rescued by TNF-α inhibition. Discussion: Our prospective observational evidence suggested that long-term exposure to PM2.5 is associated with lower BMD and further experimental results demonstrated exposure to PM2.5 could disrupt bone homeostasis, which may be mediated by inflammation-induced osteoclastogenesis. https://doi.org/10.1289/EHP11646