Ambient <math><mrow><msub><mrow><mtext>PM</mtext></mrow><mrow><mrow><mn>2.5</mn></mrow></mrow></msub></mrow></math> Exposure and Bone Homeostasis: Analysis of UK Biobank Data and Experimental Studies in Mice and in Vitro

Previous evidence has identified exposure to fine ambient particulate matter (PM2.5&lt;math&gt;&lt;mrow&gt;&lt;msub&gt;&lt;mrow&gt;&lt;mrow&gt;&lt;mi&gt;PM&lt;/mi&gt;&lt;/mrow&gt;&lt;/mrow&gt;&lt;mrow&gt;&lt;mrow&gt;&lt;mn&gt;2.5&lt;/mn&gt;&lt;/mrow&gt;&lt;/mrow&gt;&lt;/msub&gt;&lt;/mrow&gt;&lt;/math&gt;) 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&lt;math&gt;&lt;mrow&gt;&lt;msub&gt;&lt;mrow&gt;&lt;mrow&gt;&lt;mi&gt;PM&lt;/mi&gt;&lt;/mrow&gt;&lt;/mrow&gt;&lt;mrow&gt;&lt;mrow&gt;&lt;mn&gt;2.5&lt;/mn&gt;&lt;/mrow&gt;&lt;/mrow&gt;&lt;/msub&gt;&lt;/mrow&gt;&lt;/math&gt; and bone homeostasis.

Our prospective observational evidence suggested that long-term exposure to PM2.5&lt;math&gt;&lt;mrow&gt;&lt;msub&gt;&lt;mrow&gt;&lt;mrow&gt;&lt;mi&gt;PM&lt;/mi&gt;&lt;/mrow&gt;&lt;/mrow&gt;&lt;mrow&gt;&lt;mrow&gt;&lt;mn&gt;2.5&lt;/mn&gt;&lt;/mrow&gt;&lt;/mrow&gt;&lt;/msub&gt;&lt;/mrow&gt;&lt;/math&gt; is associated with lower BMD and further experimental results demonstrated exposure to PM2.5&lt;math&gt;&lt;mrow&gt;&lt;msub&gt;&lt;mrow&gt;&lt;mrow&gt;&lt;mi&gt;PM&lt;/mi&gt;&lt;/mrow&gt;&lt;/mrow&gt;&lt;mrow&gt;&lt;mrow&gt;&lt;mn&gt;2.5&lt;/mn&gt;&lt;/mrow&gt;&lt;/mrow&gt;&lt;/msub&gt;&lt;/mrow&gt;&lt;/math&gt; could disrupt bone homeostasis, which may be mediated by inflammation-induced osteoclastogenesis. https://doi.org/10.1289/EHP11646.

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&lt;math&gt;&lt;mrow&gt;&lt;msub&gt;&lt;mrow&gt;&lt;mrow&gt;&lt;mi&gt;PM&lt;/mi&gt;&lt;/mrow&gt;&lt;/mrow&gt;&lt;mrow&gt;&lt;mrow&gt;&lt;mn&gt;2.5&lt;/mn&gt;&lt;/mrow&gt;&lt;/mrow&gt;&lt;/msub&gt;&lt;/mrow&gt;&lt;/math&gt; (i.e., annual average PM2.5&lt;math&gt;&lt;mrow&gt;&lt;msub&gt;&lt;mrow&gt;&lt;mrow&gt;&lt;mi&gt;PM&lt;/mi&gt;&lt;/mrow&gt;&lt;/mrow&gt;&lt;mrow&gt;&lt;mrow&gt;&lt;mn&gt;2.5&lt;/mn&gt;&lt;/mrow&gt;&lt;/mrow&gt;&lt;/msub&gt;&lt;/mrow&gt;&lt;/math&gt; concentration for 2010) and bone mineral density [BMD; i.e., heel BMD (n=37,440&lt;math&gt;&lt;mrow&gt;&lt;mi&gt;n&lt;/mi&gt;&lt;mo&gt;=&lt;/mo&gt;&lt;mn&gt;37,440&lt;/mn&gt;&lt;/mrow&gt;&lt;/math&gt;) and femur neck and lumbar spine BMD (n=29,766&lt;math&gt;&lt;mrow&gt;&lt;mi&gt;n&lt;/mi&gt;&lt;mo&gt;=&lt;/mo&gt;&lt;mn&gt;29,766&lt;/mn&gt;&lt;/mrow&gt;&lt;/math&gt;)], which were measured during 2014-2020. For the experimental animal study, C57BL/6 male mice were assigned to ambient PM2.5&lt;math&gt;&lt;mrow&gt;&lt;msub&gt;&lt;mrow&gt;&lt;mrow&gt;&lt;mi&gt;PM&lt;/mi&gt;&lt;/mrow&gt;&lt;/mrow&gt;&lt;mrow&gt;&lt;mrow&gt;&lt;mn&gt;2.5&lt;/mn&gt;&lt;/mrow&gt;&lt;/mrow&gt;&lt;/msub&gt;&lt;/mrow&gt;&lt;/math&gt; 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&lt;math&gt;&lt;mrow&gt;&lt;msub&gt;&lt;mrow&gt;&lt;mrow&gt;&lt;mi&gt;PM&lt;/mi&gt;&lt;/mrow&gt;&lt;/mrow&gt;&lt;mrow&gt;&lt;mrow&gt;&lt;mn&gt;2.5&lt;/mn&gt;&lt;/mrow&gt;&lt;/mrow&gt;&lt;/msub&gt;&lt;/mrow&gt;&lt;/math&gt; exposure on osteoclast activity in vitro. In addition, the potential downstream regulators were assessed by real-time polymerase chain reaction and western blot.

We sought to examine the relationship between long-term PM2.5&lt;math&gt;&lt;mrow&gt;&lt;msub&gt;&lt;mrow&gt;&lt;mrow&gt;&lt;mi&gt;PM&lt;/mi&gt;&lt;/mrow&gt;&lt;/mrow&gt;&lt;mrow&gt;&lt;mrow&gt;&lt;mn&gt;2.5&lt;/mn&gt;&lt;/mrow&gt;&lt;/mrow&gt;&lt;/msub&gt;&lt;/mrow&gt;&lt;/math&gt; exposure and bone health and explore its potential mechanism.

We observed that long-term exposure to PM2.5&lt;math&gt;&lt;mrow&gt;&lt;msub&gt;&lt;mrow&gt;&lt;mrow&gt;&lt;mi&gt;PM&lt;/mi&gt;&lt;/mrow&gt;&lt;/mrow&gt;&lt;mrow&gt;&lt;mrow&gt;&lt;mn&gt;2.5&lt;/mn&gt;&lt;/mrow&gt;&lt;/mrow&gt;&lt;/msub&gt;&lt;/mrow&gt;&lt;/math&gt; 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&lt;math&gt;&lt;mrow&gt;&lt;msub&gt;&lt;mrow&gt;&lt;mrow&gt;&lt;mi&gt;PM&lt;/mi&gt;&lt;/mrow&gt;&lt;/mrow&gt;&lt;mrow&gt;&lt;mrow&gt;&lt;mn&gt;2.5&lt;/mn&gt;&lt;/mrow&gt;&lt;/mrow&gt;&lt;/msub&gt;&lt;/mrow&gt;&lt;/math&gt; exhibited excessive osteoclastogenesis, dysregulated osteogenesis, higher tumor necrosis factor-alpha (TNF-α&lt;math&gt;&lt;mrow&gt;&lt;mtext&gt;TNF-&lt;/mtext&gt;&lt;mi&gt;α&lt;/mi&gt;&lt;/mrow&gt;&lt;/math&gt;) 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&lt;math&gt;&lt;mrow&gt;&lt;msub&gt;&lt;mrow&gt;&lt;mrow&gt;&lt;mi&gt;PM&lt;/mi&gt;&lt;/mrow&gt;&lt;/mrow&gt;&lt;mrow&gt;&lt;mrow&gt;&lt;mn&gt;2.5&lt;/mn&gt;&lt;/mrow&gt;&lt;/mrow&gt;&lt;/msub&gt;&lt;mtext&gt;-stimulated&lt;/mtext&gt;&lt;/mrow&gt;&lt;/math&gt; macrophages had aberrant osteoclastogenesis and differences in the protein/mRNA expression of members of the TNF-α/Traf6/c-Fos&lt;math&gt;&lt;mrow&gt;&lt;mtext&gt;TNF-&lt;/mtext&gt;&lt;mi&gt;α&lt;/mi&gt;&lt;mo&gt;/&lt;/mo&gt;&lt;mtext&gt;Traf&lt;/mtext&gt;&lt;mn&gt;6&lt;/mn&gt;&lt;mo&gt;/&lt;/mo&gt;&lt;mi&gt;c&lt;/mi&gt;&lt;mtext&gt;-Fos&lt;/mtext&gt;&lt;/mrow&gt;&lt;/math&gt; pathway, which could be partially rescued by TNF-α&lt;math&gt;&lt;mrow&gt;&lt;mtext&gt;TNF-&lt;/mtext&gt;&lt;mi&gt;α&lt;/mi&gt;&lt;/mrow&gt;&lt;/math&gt; inhibition.