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 syno-vial 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,-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 25% and 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.

Inflammation is preceded by tumor necrosis factor‐dependent infiltration of mesenchymal cells in experimental arthritis

“…Immunolocalization of BMPR was carried out as previously described (1). Briefly, hind paws were embedded in OCT embedding matrix (Cell Path, Hemel Hemstead, UK) and then snap frozen.…”

“…For example, during organogenesis of mouse embryos, cells expressing BMPRIA and BMPRIB can be demonstrated in areas of mesenchymal precartilage condensation and in premuscle or on cells in areas of developing cartilage and bone. In previous studies we have used anti-BMPR antibodies to characterize a population of MPCs in the blood of healthy individuals (8) and in the synovial tissue of patients with RA (1).…”

How important are T cells in chronic rheumatoid synovitis?: II. T cell‐independent mechanisms from beginning to end

“…RA synovial tissues contain osteoclasts at sites remote from bone and in the pannus adjacent to bone erosions. Monocytes and bone morphogenetic protein receptor-bearing cells also reside in the same locations (77). In vitro, long-term culture of freshly isolated RA synovial tissues or coculture of adherent RA FLS with peripheral blood mononuclear cells leads to the formation of bone-resorbing multinucleated cells, but neither osteoarthritis FLS nor dermal fibroblasts form similar cells (86)(87)(88).…”

Engineering mesenchymal stem cells for immunotherapy

“…33,34 In experimental CIA, MSCs were found in the joints of animals at 2 weeks before the onset of the disease. At that time, synovial hyperplasia was associated to an increase of medullar cells in the epiphyseal region and formation of canals between the bone marrow and the joint cavity.…”