Background/Purpose: Proinflammatory cytokines play an important role in bone destruction in rheumatoid arthritis (RA), as inferred by the efficacy of biologics. Previously, we reported that novel osteoclast-like cells (OLCs) were induced, both in vitro and in vivo, from mouse bone marrow-derived macrophages by a combination of TNFα and IL-6 (Yokota K et al., Arthritis Rheumatol 2014, 66:121-129). Herein, we aimed to examine the differentiation of OLCs, which were induced by a combination of TNFα and IL-6 from human peripheral blood mononuclear cells (PBMCs) and CD14+ monocytes and to identify differences in molecular expression patterns between OLCs and conventional osteoclasts. Furthermore, we identified OLCs and osteoclasts on the bone tissue of the joint in patients with RA.

Methods: PBMCs and CD14+ monocytes from healthy volunteers and/or RA patients were stimulated with TNFα and IL-6 or RANKL. Quantitative RT-PCR was used to measure mRNA expression levels of osteoclastogenesis-related genes. Prepared undecalcified tibial bone from 6 RA or osteoarthritis (OA) patients undergoing joint surgery were stained by tartrate-resistant acid phosphatase (TRAP) staining and immunohistochemistry with anti-RANK antibody, expression of which were analyzed. Osteoclasts and OLCs were identified as multinucleated TRAP+/RANK+ cells and TRAP+/RANK- cells, respectively, adherent to the bone surface.

Results: The number of osteoclasts treated with RANKL and OLCs treated with a combination of TNFα and IL-6 from PBMCs or CD14+ monocytes in RA patients was significantly increased compared to that in healthy volunteers. Expression levels of TRAP mRNA was clearly up-regulated in osteoclasts and OLCs compared to that in osteoclast precursors. On the other hand, expression levels of RANK mRNA was obviously up-regulated in osteoclasts, and was down-regulated in OLCs. In cancellous bone, the number of TRAP+/RANK+ osteoclasts and TRAP+/RANK- OLCs was significantly increased in RA patients compared to that in OA patients. Interestingly, numerous TRAP+/RANK- OLCs were present in the cancellous bone of RA patients, while almost none were observed in the cancellous bone of OA patients.

Conclusion: The combination of TNFα and IL-6 strongly induced the differentiation of OLCs from PBMCs or CD14+ monocytes in RA patients. OLCs was characterized with TRAP+/RANK- multinucleated cells, which can be distinguished from conventional TRAP+/RANK+ multinucleated osteoclasts. TRAP+/RANK- OLCs also were present in the bone tissue of RA patients. These results suggest that conventional osteoclasts and novel OLCs could be involved in the pathogenic mechanisms of inflammatory bone destruction such as RA.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/detection-of-precursors-of-rank-osteoclast-like-cells-olcs-in-peripheral-blood-and-olcs-in-bone-tissue-from-rheumatoid-arthritis-patients/