Background/Purpose: Bone destruction in rheumatoid arthritis is mediated by osteoclasts, which are derived from precursor cells of the myeloid lineage.  Although there is much known about mature osteoclasts, the identity of an osteoclast precursor population and its regulation by inflammatory cytokines during arthritis is poorly understood.

Methods: HTNFtg mice were clinically scored once per week for grip strength and swelling. In addition, blood was collected every other week starting on week 4. Mice were sacrificed at week 10 – blood, spleen and bone marrow were collected for flow cytometry analysis. K/BxN Arthritis was induced in wild type mice, blood and spleen were collected 14 days after disease induction. HTNFtg/CCR2^-/-and hTNFtg mice were analyzed histologically. Different monocyte subsets were Facs-sorted and cultured in the presence of RANKL and MCSF to induce osteoclasts.

Results: Here we show that during TNF-driven arthritis monocytes, in particular resident non-classical monocytes (CD115⁺Ly6C^lowCCR2^–), are elevated in blood before the onset of clinical symptoms and remain elevated throughout. Upon sorting resident and inflammatory monocytes (CD115⁺Ly6C^highCCR2⁺) from blood, we demonstrate that resident monocytes are more potent to form osteoclasts ex vivo. In addition, the number of resident monocytes in blood positively correlated with histological signs of joint destruction, such as area of erosion and number of osteoclasts in arthritic hind paws, while the number of inflammatory monocytes did not correlate at all with those parameters. Of note, we observed a similar correlation of resident monocytes with histological markers of tissue damage also in another model of inflammatory arthritis, K/BxN serum transfer arthritis. Next, we crossed CCR2 deficient mice, which lack circulating inflammatory monocytes, into hTNFtg animals. In line with our hypothesis that resident monocytes are mediating local bone destruction, hTNFtg mice lacking CCR2 showed no decrease but even enhanced local bone erosion and osteoclast generation. 

Conclusion: Resident non classical monocytes with osteoclastogenic potential are elevated during chronic inflammatory arthritis and the numbers in blood correlate with histological markers of joint destruction in models of inflammatory arthritis in two models of arthritis. Therefore these cells may provide a biomarker for erosive inflammatory arthritis and even a possible target for therapeutically intervention.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/resident-non-classical-monocytes-are-critically-important-for-tissue-destruction-in-arthritis/