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. 2006;8(3):R58.
doi: 10.1186/ar1923. Epub 2006 Mar 15.

Decrease in expression of bone morphogenetic proteins 4 and 5 in synovial tissue of patients with osteoarthritis and rheumatoid arthritis

Carsten P Bramlage  1 , Thomas Häupl, Christian Kaps, Ute Ungethüm, Veit Krenn, Axel Pruss, Gerhard A Müller, Frank Strutz, Gerd-R Burmester
Affiliations

Decrease in expression of bone morphogenetic proteins 4 and 5 in synovial tissue of patients with osteoarthritis and rheumatoid arthritis

Carsten P Bramlage et al. Arthritis Res Ther. 2006.

Abstract

Bone morphogenetic proteins (BMPs) have been identified as important morphogens with pleiotropic functions in regulating the development, homeostasis and repair of various tissues. The aim of this study was to characterize the expression of BMPs in synovial tissues under normal and arthritic conditions. Synovial tissue from normal donors (ND) and from patients with osteoarthritis (OA) and rheumatoid arthritis (RA) were analyzed for BMP expression by using microarray hybridization. Differential expression of BMP-4 and BMP-5 was validated by semiquantitative RT-PCR, in situ hybridization and immunohistochemistry. Activity of arthritis was determined by routine parameters for systemic inflammation, by histological scoring of synovitis and by semiquantitative RT-PCR of IL-1beta, TNF-alpha, stromelysin and collagenase I in synovial tissue. Expression of BMP-4 and BMP-5 mRNA was found to be significantly decreased in synovial tissue of patients with RA in comparison with ND by microarray analysis (p < 0.0083 and p < 0.0091). Validation by PCR confirmed these data in RA (p < 0.002) and also revealed a significant decrease in BMP-4 and BMP-5 expression in OA compared with ND (p < 0.015). Furthermore, histomorphological distribution of both morphogens as determined by in situ hybridization and immunohistochemistry showed a dominance in the lining layer of normal tissues, whereas chronically inflamed tissue from patients with RA revealed BMP expression mainly scattered across deeper layers. In OA, these changes were less pronounced with variable distribution of BMPs in the lining and sublining layer. BMP-4 and BMP-5 are expressed in normal synovial tissue and were found decreased in OA and RA. This may suggest a role of distinct BMPs in joint homeostasis that is disturbed in inflammatory and degenerative joint diseases. In comparison with previous reports, these data underline the complex impact of these factors on homeostasis and remodeling in joint physiology and pathology.

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Figures

Figure 1
Figure 1
Expression of TNF-α, IL-1β, stromelysin and collagenase I in synovial tissues. Results are presented as percentage of GAPDH expression on a logarithmic scale with maximum, minimum, quartiles and median. Where indicated with an asterisk, there were significant differences from normal tissues (p < 0.05; Mann–Whitney). Rheumatoid arthritis (RA) versus normal donors (ND): IL-1β, p = 0.0097; TNF-α, p = 0.008; stromelysin, p = 0.0009; collagenase I, p = 0.0002. Osteoarthritis (OA) versus ND: IL-1β, p = 0.1451; TNF-α, p = 0.0013; stromelysin, p = 0.038; collagenase I, p = 0.0012. RA versus OA: IL-1β, p = 0.0397; TNF-α, p = 0.9591; stromelysin, p = 0.0124; collagenase I, p = 0.0266. GAPDH, glyceraldehyde-3-phosphate dehydrogenase.
Figure 2
Figure 2
Expression of BMP-4 and BMP-5 in synovial tissues detected by microarray technique. Results are presented on a logarithmic scale with maximum, minimum, quartiles and median. Where indicated with an asterisk, there were significant differences from normal tissues (p < 0.05; t test). Rheumatoid arthritis (RA) versus normal donors (ND): bone morphogenetic protein (BMP)-4, p = 0.0009 (adjusted p ≤ 0.0083); BMP-5, p = 0.0142 (probe set ID 205431_s_at; data not shown) and p = 0.006 (probe set ID 205430_at) (adjusted p ≤ 0.009). Osteoarthritis (OA) versus ND: BMP-4, p = 0.854; BMP-5, p = 0.216 (probe set ID 205431_s_at) and p = 0.129 (probe set ID 205430_at) (no significance). RA versus OA: BMP-4, p = 0.000003 (adjusted p ≤ 0.0083); BMP-5, p = 0.2391 (probe set ID 205431_s_at) and p = 0.026 (probe set ID 205430_at) (no significance).
Figure 3
Figure 3
Expression of BMP-4 and BMP-5 in synovial tissues detected by semiquantitative PCR. Results are presented as percentage of GAPDH expression on a logarithmic scale with maximum, minimum, quartiles and median. Where indicated, there were significant differences from normal tissues (asterisk) or osteoarthritis (OA) (hash sign) (p < 0.05, Mann–Whitney). Rheumatoid arthritis (RA) versus normal donors (ND): bone morphogenetic protein (BMP)-4, p = 0.0005; BMP-5, p = 0.0016. OA versus ND: BMP-4, p = 0.0143; BMP-5, p = 0.0011. RA versus OA: BMP-4, p = 0.0180; BMP-5, p = 0.9215. GAPDH, glyceraldehyde-3-phosphate dehydrogenase.
Figure 4
Figure 4
Immunohistochemistry and in situ hybridization of synovial tissues for BMP-4. In normal synovial tissue the expression of bone morphogenetic protein (BMP) is localized to the synovial lining layer. In rheumatoid arthritis (RA) and osteoarthritis (OA) tissue samples BMP-4 is expressed less by cells of the superficial synovial layer but more by cells scattered in deeper layers. Original magnifications: immunohistochemistry (IMH): RA, normal donors (ND) ×40, OA ×20; in situ hybridization (ISH): RA, OA, ND ×40.
Figure 5
Figure 5
Immunohistochemistry (IMH) and in situ hybridization (ISH) of synovial tissues for BMP-5. Histomorphological distribution of BMP-5 is comparable to that of BMP-4 (Figure 4). Original magnifications: immunohistochemistry (IMH): rheumatoid arthritis (RA), osteoarthritis (OA), normal donors (ND) ×20; in situ hybridization (ISH): RA, OA, ND ×40. BMP, bone morphogenetic protein.
Figure 6
Figure 6
Expression of BMP-4 in fibroblastoid (black arrow) and macrophagocytic (white arrow) cells by immunohistochemistry. Original magnifications: normal donors (ND), rheumatoid arthritis (RA) ×100. BMP, bone morphogenetic protein.
Figure 7
Figure 7
Fibroblasts (black arrows) expressing bone morphogenetic protein (BMP)-4 (a) and BMP-5 (b) in areas with fibrosis in osteoarthritis synovial tissue (original magnification ×20). Macrophagocytic (white arrows) and fibroblastoid (black arrows) appearance of cells adjacent to vessels (V) expressing BMP-4 (c) and BMP-5 (d) in rheumatoid arthritis synovial tissues (original magnification ×40).
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