Ambient ${\text{PM}}_{2.5}$ 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 (${\mathrm{PM}}_{2.5}$) 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 ${\mathrm{PM}}_{2.5}$ and bone homeostasis.

Objective: We sought to examine the relationship between long-term ${\mathrm{PM}}_{2.5}$ 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 ${\mathrm{PM}}_{2.5}$ (i.e., annual average ${\mathrm{PM}}_{2.5}$ concentration for 2010) and bone mineral density [BMD; i.e., heel BMD ($n=\mathrm{37,440}$) and femur neck and lumbar spine BMD ($n=\mathrm{29,766}$)], which were measured during 2014-2020. For the experimental animal study, C57BL/6 male mice were assigned to ambient ${\mathrm{PM}}_{2.5}$ 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 ${\mathrm{PM}}_{2.5}$ 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 ${\mathrm{PM}}_{2.5}$ 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 ${\mathrm{PM}}_{2.5}$ exhibited excessive osteoclastogenesis, dysregulated osteogenesis, higher tumor necrosis factor-alpha ($\text{TNF-}\alpha$) 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 ${\mathrm{PM}}_{2.5}\text{-stimulated}$ macrophages had aberrant osteoclastogenesis and differences in the protein/mRNA expression of members of the $\text{TNF-}\alpha /\text{Traf}6/c\text{-Fos}$ pathway, which could be partially rescued by $\text{TNF-}\alpha$ inhibition.

Discussion: Our prospective observational evidence suggested that long-term exposure to ${\mathrm{PM}}_{2.5}$ is associated with lower BMD and further experimental results demonstrated exposure to ${\mathrm{PM}}_{2.5}$ could disrupt bone homeostasis, which may be mediated by inflammation-induced osteoclastogenesis. https://doi.org/10.1289/EHP11646.