Detection, identification and in vivo treatment responsiveness of bone morphogenetic protein (BMP)-activated cell populations in the synovium of patients with rheumatoid arthritis.
OBJECTIVE
To characterise the bone morphogenetic protein (BMP) target cells positive for phosphorylated (P)-SMAD1/5, in rheumatoid arthritis (RA) synovium.


METHODS
Synovial biopsies were obtained by needle arthroscopy. Anti-P-SMAD1/5 antibodies were used for Western blot (WB) on protein extracts from RA and normal synovium and for immunostaining of synovial biopsy sections. Positive cells were further identified by double staining for CD3, CD20, CD68, CD138, CD90, alpha smooth muscle actin (SMA), endoglin (CD105) and von Willebrand factor (VWF). In sections from early patients with RA taken before and under antirheumatic treatment, the degree of inflammation and activation of the BMP pathway were quantified.


RESULTS
P-SMAD1/5 protein was detected by WB in RA and to a lesser extent in normal synovium. Different P-SMAD1/5 positive cell populations were identified in RA synovium, mainly in perivascular and sublining cells. P-SMAD1/5 positive perivascular cells were alphaSMA positive and located around VWF positive endothelial cells. Some CD90 positive synovial fibroblasts were P-SMAD1/5 positive, as was part of the CD68 positive synovial cells but other cells of the haematopoietic lineage showed no SMAD1/5 phosphorylation. Treatment resulted in an absolute but not relative decrease in BMP activation in the synovium.


CONCLUSIONS
BMP-activated cells belong to distinct stromal compartments in RA synovium and some of them express markers associated with the mesenchymal progenitor cell lineage. Antirheumatic treatment effectively downregulates synovial inflammation, but BMP activation in the synovium does persist albeit reduced.
Verschueren
P C P M
PC
Laboratory for Skeletal Development and Joint Disorders, Division of Rheumatology Department of Musculoskeletal Sciences, Katholieke Universiteit Leuven, Belgium.
Lories
R J U
RJ
Daans
M
M
Théate
I
I
Durez
P
P
Westhovens
R
R
Luyten
F P
FP
D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000032:analysis; D015214:Antigens, Differentiation, Myelomonocytic / Q000032:analysis; D018501:Antirheumatic Agents / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000276:immunology / Q000473:pathology*; D015415:Biomarkers / Q000032:analysis; D015153:Blotting, Western; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D016022:Case-Control Studies; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D010750:Phosphoproteins / Q000032:analysis; D010766:Phosphorylation; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D051896:Smad Proteins, Receptor-Regulated / Q000032:analysis / Q000378:metabolism*; D051898:Smad1 Protein / Q000032:analysis; D051902:Smad5 Protein / Q000032:analysis; D018709:Statistics, Nonparametric; D013268:Stimulation, Chemical; D013583:Synovial Membrane / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D018800:Thy-1 Antigens / Q000032:analysis; D016896:Treatment Outcome; D014841:von Willebrand Factor / Q000032:analysis; D000097382:CD68 Molecule
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D018501:Antirheumatic Agents; D015415:Biomarkers; D019485:Bone Morphogenetic Proteins; D010750:Phosphoproteins; D051896:Smad Proteins, Receptor-Regulated; D051898:Smad1 Protein; D051902:Smad5 Protein; D018800:Thy-1 Antigens; D014841:von Willebrand Factor; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C497399:SMAD1 protein, human; C497797:SMAD5 protein, human