Why arthritis affects some joints and not others, or even specific sites within joints, has long remained an unsolved mystery. Ideas have ranged from site-specific differences in stromal cells to the affinity of autoantibodies for cells in the joints. New research published in Nature Communications is championing the response of stromal cells to biomechanical strain as a vital factor in the development of arthritis at specific locations.

Lateral view of micro-CT scans of mice with collagen-induced arthritis under unloaded (left) and voluntary-running conditions (right). Adapted from Cambré, I. et al. Mechanical strain determines the site-specific localization of inflammation and tissue damage in arthritis. Nat. Commun. 9, 4613 (2018), CC-BY-4.0.

“This work was initially inspired by our previous finding that in a mouse model of spondyloarthritis (SpA), the TNFΔARE model, enthesitis was lacking in mice that had undergone hind limb unloading,” explains corresponding author Dirk Elewaut. “We therefore thought this might be a general concept that could be applicable to other inflammatory arthritides such as rheumatoid arthritis (RA).”

To test this theory, Elewaut and colleagues investigated the effects of decreasing and increasing joint loading (via hind limb unloading and voluntary running, respectively) on the development of collagen-induced arthritis (CIA) in mice. Disease was almost completely abrogated in the unloaded hind limbs of mice with CIA, whereas arthritis onset was accelerated in voluntary-running mice. Disease was also exacerbated in voluntary-running TNFΔARE mice (in which TNF is overexpressed) compared with control mice (housed without access to a wheel). Similar results were also seen in mice with collagen antibody-induced arthritis (CAIA).

Linking biomechanical strain to inflammation, the researchers analysed gene expression arrays of Achilles tendon cells from healthy mice. Expression of chemokines and pro-inflammatory cytokines was increased in the tendons of voluntary-running mice but not of control mice. These findings were confirmed in vitro by stretching fibroblasts that had been grown on a flexible membrane, which prompted them to produce the chemokine CCL2 and thereby to recruit monocytes. Voluntary-running TNFΔARE mice also had increased numbers of monocytes in their synovium. Furthermore, in mice lacking CCL2, voluntary running did not exacerbate CAIA, suggesting a role for monocytes in initiating arthritis at mechanosensitive sites.

Using μCT imaging, the researchers identified areas of the joint that were prone to developing bone erosions during arthritis. These areas contained a large number of tendon attachments, so were probably particularly sensitive to biomechanical strain.

Interestingly, similar patterns of bone erosion at sites of high biomechanical strain were seen in the feet of patients with RA or SpA. “This is a very significant finding in our opinion, as it explains to a large degree the patchy nature of joint inflammation in human arthritides and the clinical pattern of joint involvement,” says Elewaut.