Mesenchymal cells expressing bone morphogenetic protein receptors are present in the rheumatoid arthritis joint

Abstract

Objective: To evaluate the presence of cells of an early mesenchymal lineage, as judged by the expression of bone morphogenetic protein receptors (BMPRs), in the joints of normal individuals and patients with rheumatoid arthritis (RA).

Methods: Synovial fluids, single cell suspensions of cultured fibroblast-like synoviocytes (FLS), and synovial tissues were examined by immunohistology with antibodies to BMPR type IA (BMPRIA), BMPRIB, and BMPRII and then quantified using computerized image analysis. Other antibodies were evaluated by cytofluorography.

Results: In primary cultures of joint effusions from patients with RA and other forms of inflammatory arthritis, there were large adherent cells with the appearance of either fibroblasts or stromal cells that stained with antibodies to mesenchymal elements-CD44, type I collagen, alpha-actin, and vimentin-but not with antibodies to hematopoietic markers. These cells proliferated rapidly, expressed BMPRIA and BMPRII, and soon became the predominant cells in culture. They were retained through multiple passages and persistently displayed surface vascular cell adhesion molecule 1. Immunohistochemical analysis of cultured RA FLS (passages 3, 4, and 6; n = 6) revealed that 11.6% were BMPR-positive, while only 2.0% of osteoarthritis FLS (passage 4; n = 3) were BMPR-positive, and 1 normal synovial culture had no BMPR-positive cells. In all RA synovial membranes examined (n = 9), BMPRI- and BMPRII-expressing cells were identified in the intimal lining and were also scattered in the subintima. These cells constituted approximately 25% and approximately 7% of the cells in each area, respectively. Double immunostaining showed no coexpression of BMPR-positive cells with CD68, CD34, or CD3. Cells expressing BMPR were not seen in any normal synovial samples (n = 4). Strong staining for BMPR was identified on cells at the invasive front of the pannus and at sites of cartilage erosion.

Conclusion: The inflamed RA joint contains BMPR-positive mesenchymal cells. Their origin is still speculative, but since their counterparts in the bone marrow are essential for osteoclastogenesis, support lymphocyte development and maturation, and protect T cells and B cells from programmed cell death, the BMPR-positive cells may be essential elements in the pathogenesis of RA and other inflammatory forms of chronic synovitis.