Potentional role of selected biomarkers in the evaluation and pathogenesis of osteoarthritis and rheumatoid arthritis

Authors: L. Šenolt
Authors‘ workplace: Revmatologický ústav Praha
Published in: Čes. Revmatol., 15, 2007, No. 1, p. 13-24.
Category: Summaries of Doctoral Dissertations


Rheumatoid arthritis (RA) and osteoarthritis (OA) represent the most common forms of musculosceletal disorders that affect diarthrodial joints, often lead to joint damage and disability. Diagnosis of both conditions is based on the conventional radiography. Mostly in OA, radiographic changes often occur late in the disease and are largely irreversible. Current investigation revealed potential uses of molecular markers, ranging from understanding pathogenesis of the diseases to predicting and monitoring the outcome of the treatment. Molecular markers could reflect joint damage, inflammation, or immune response. The aim of the thesis was to analyze several biochemical markers in serum, synovial fluid and synovial tissue samples from patients with RA and OA, and to evaluate their diagnostic and predictive values as well as their contribution to the pathogenesis of the diseases. We found an increased serum pentosidine concentration in knee OA patients that was of predictive value of the joint space narrowing. Moreover, positive correlation between pentosidine and cartilage oligomeric matrix protein (COMP) in synovial fluid makes pentosidine one of the new potential biomarkers of the OA. Serum level of COMP was similar among patients with OA and RA as well as healthy individuals. In our study, COMP in serum was not predictive for further progression of OA and did not correlate with any marker of inflammation both in OA and RA. On the other side, COMP was significantly elevated in OA synovial fluid in contrast to RA synovial fluid, which may reflect distinct pathogenic feature of cartilage loss in OA process. Relationship between modulator of bone metabolism osteoprotegerin (OPG) and marker of bone turnover deoxypyridinolin in serum from OA patients could represent a balance between bone-protective role of OPG and bone resorption. In RA patients significantly elevated levels of pentosidine were associated neither with CRP nor with disease activity. Relationships between COMP and anti-CCP antibodies in serum, COMP and OPG in synovial fluid may reflect the association of systemic cartilage turnover and immune activity, and local cartilage destruction and bone metabolism in RA. Decreased levels of OPG in RA can be responsible for the periarticular osteoporosis, bone destruction observed in RA, and thus predicate an insufficient bone-protective role of OPG in inflammatory diseases. Moreover, we found the expression of metastasis-inducing protein - S100A4 at sites of invasion in RA synovium. In addition, exogenous S100A4 modulated expression and production of several matrix metalloproteinases (MMP) by RA synovial fibroblasts. Since several phenomena are similar between RA and malignant tumors, it can be hypothesized that S100A4 contributes to the aggressive, invasive, and tumor-like behavior of RA synovium. In conclusion, pentosidine may represent new biochemical marker of OA progression. Increased COMP in synovial fluid from OA patients can be a result of a different pathogenic feature of cartilage destruction in OA compared to RA. A relationship between several cartilage, bone, and immunological markers in RA could show a complexity of the disease. S100A4 could represent a new molecule that might be implicated in the pathogenesis of RA.

Key words:
rheumatoid arthritis, osteoarthritis, pentosidine, cartilage oligomeric matrix protein, osteoprotegerin, antibodies against cyclic citrulinated peptide, S100A4


1. Lawrence RC, Helmick GG, Arnett DF, et al. Estimates of the prevalence of arthritis and selected musculosceletal disorders in the United States. Arthritis Rheum 1998; 41: 778–788.

2. Lajeunesse D, Reboul P. Subchondral bone in osteoarthritis: a biologic link with articular cartilage leading to abnormal remodeling. Curr Opin Rheumatol 2003; 15: 628–33.

3. Zvaifler NJ, Firestein GS. Pannus and pannocytes. Alternative models of joint destruction in rheumatoid arthritis. Arthritis Rheum 1994; 37: 783–9.

4. Garnero P. Osteoarthritis: biological markers for the future? Joint Bone Spine 2002; 69: 525–30.

5. Mulherin D, Fitzgerald O, Bresnihan B. Clinical improvement and radiological deterioration in rheumatoid arthritis: evidence that the pathogenesis of synovial inflammation and articular erosion may differ. Br J Rheumatol 1996; 35: 1263–8.

6. Prevoo ML, van ‘t Hof MA, Kuper HH, van Leeuwen MA, van de Putte LB, van Riel PL. Modified disease activity scores that include twenty-eight-joint counts. Development and validation in a prospective longitudinal study of patients with rheumatoid arthritis. Arthritis Rheum 1995; 38: 44–8.

7. Ramey DR, Raynauld JP, Fries JF. The health assessment questionnaire 1992: status and review. Arthritis Care Res 1992; 5: 119–29.

8. Angst F, Aeschlimann A, Steiner W, Stucki G. Responsiveness of the WOMAC osteoarthritis index as compared with the SF-36 in patients with osteoarthritis of the legs undergoing a comprehensive rehabilitation intervention. Ann Rheum Dis 2001; 60: 834–40.

9. Kellgren JH, Lawrence JS. Radiological assessment of osteoarthritis. Ann Rheum Dis 1957; 16: 494–501.

10. Altman R, Asch E, Bloch D, et al. Development of criteria for the classification and reporting of osteoarthritis. Classification of osteoarthritis of the knee. Diagnostic and Therapeutic Criteria Committee of the American Rheumatism Association. Arthritis Rheum 1986; 29: 1039–49.

11. Steinbrocker O, Traeger CH, Batterman RC. Therapeutic criteria in rheumatoid arthritis JAMA 1949; 140: 659–62.

12. Chen JR, Takahashi M, Suzuki M, Kushida K, Miyamoto S, Inoue T. Comparison of the concentrations of pentosidine in the synovial fluid, serum and urine of patients with rheumatoid arthritis and osteoarthritis. Br J Rheumatol 1999; 38: 1275–78.

13. Verzijl N, Bank RA, TeKoppele JM, DeGroot J. AGEing and osteoarthritis: a different perspective. Curr Opin Rheumatol 2003; 15: 616–22.

14. Gibson GJ, Verner JJ, Nelson FR, Lin DL. Degradation of the cartilage collagen matrix associated with changes in chondrocytes in osteoarthrosis. Assessment by loss of background fluorescence and immunodetection of matrix components. J Orthop Res 2001; 19: 33–42.

15. Pelletier JP, Pelletier JM, Abramson SB. Osteoarthritis, an Inflammatory Disease. Arthritis Rheum 2001; 44: 1237–1247.

16. Sturmer T, Brenner H, Koenig W, Gunther KP. Severity and extent of osteoarthritis and low grade systemic inflammation as assessed by high sensitivity C reactive protein. Ann Rheum Dis 2004; 63: 200–5.

17. Saxne T, Heinegard D. Cartilage oligomeric matrix protein: a novel marker of cartilage turnover detectable in synovial fluid and blood. Br J Rheumatol 1992; 31: 583–91.

18. Pertynska-Marczewska M, Kiriakidis S, Wait R, Beech J, Feldmann M, Paleolog EM. Advanced glycation end products upregulate angiogenic and pro-inflammatory cytokine production in human monocyte/macrophages. Cytokine 2004; 28: 35–47.

19. Verzijl N, DeGroot J, Oldehinkel E, et al. Age-related accumulation of Maillard reaction products in human articular cartilage collagen. Biochem J 2000; 350: 381–387.

20. DeGroot J, Verzijl N, Wenting-van Wijk MJ, et al. Accumulation of advanced glycation end products as a molecular mechanism for aging as a risk factor in osteoarthritis. Arthritis Rheum 2004; 50: 1207–15.

21. Špaček P, Adam M. HPLC method for pentosidine determination in urine, serum, and tissues as a marker of glycation and oxidation loading of the organism. J Liq Chrom.Rel.Technol 2002; 25: 1807–20.

22. Takahashi M, Kushida K, Ohishi T, et al. Quantitative analysis of crosslinks pyridinoline and pentosidine in articular cartilage of patients with bone and joint disorders. Arthritis Rheum 1994; 37: 724–8.

23. Chen JR, Takahashi M, Suzuki M, Kushida K, Miyamoto S, Inoue T. Comparison of the concentrations of pentosidine in the synovial fluid, serum and urine of patients with rheumatoid arthritis and osteoarthritis. Br J Rheumatol 1999; 38: 1275–78.

24. Vincent C, Nogueira L, Clavel C, Sebbag M, Serre G. Autoantibodies to citrullinated proteins: ACPA. Autoimmunity 2005; 38: 17–24.

25. Vencovský J, Macháček S, Šedová L, et al. Autoantibodies can be prognostic markers of an erosive disease in early rheumatoid arthritis. Ann Rheum Dis 2003; 62: 427–30.

26. Jordan JM, Luta G, Stabler T, et al. Ethnic and sex differences in serum levels of cartilage oligomeric matrix protein: the Johnston County Osteoarthritis Project. Arthritis Rheum 2003; 48: 675–81.

27. Vilím V, Olejárová M, Macháček S, Gatterová J, Kraus VB, Pavelka K. Serum levels of cartilage oligomeric matrix protein (COMP) correlate with radiographic progression of knee osteoarthritis. Osteoarthritis cartilage 2002; 10: 707–13.

28. Soderlin MK, Kastbom A, Kautiainen H, Leirisalo-Repo M, Strandberg G, Skogh T. Antibodies against cyclic citrullinated peptide (CCP) and levels of cartilage oligomeric matrix protein (COMP) in very early arthritis: relation to diagnosis and disease activity. Scand J Rheumatol 2004; 33: 185–8.

29. Roux-Lombard P, Eberhardt K, Saxne T, Dayer JM, Wollheim FA. Cytokines, metalloproteinases, their inhibitors and cartilage oligomeric matrix protein: relationship to radiological progression and inflammation in early rheumatoid arthritis. A prospective 5-year study. Rheumatology (Oxford) 2001; 40(5): 544–51.

30. Yano K, Tsuda E, Washida N, et al. Immunological characterization of circulating osteoprotegerin/osteoclastogenesis inhibitory factor: increased serum concentrations in postmenopausal women with osteoporosis. J Bone Miner Res 1999; 14: 518–27.

31. Haynes DR, Barg E, Crotti TN, et al. Osteoprotegerin expression in synovial tissue from patients with rheumatoid arthritis, spondyloarthropathies and osteoarthritis and normal controls. Rheumatology (Oxford) 2003; 42: 123–34.

32. Crotti TN, Smith MD, Weedon H, et al. Receptor activator NF-kappaB ligand (RANKL) expression in synovial tissue from patients with rheumatoid arthritis, spondyloarthropathy, osteoarthritis, and from normal patients: semiquantitative and quantitative analysis. Ann Rheum Dis 2002; 61: 1047–54.

33. Helfman DM, Kim EJ, Lukanidin E, Grigorian M. The metastasis associated protein S100A4: role in tumour progression and metastasis. Br J Cancer 2005; 92: 1955–8.

34. Schmidt-Hansen B, Klingelhofer J, Grum-Schwensen B, et al. Functional significance of metastasis-inducing S100A4(Mts1) in tumor-stroma interplay. J Biol Chem 2004; 279: 24498–504.

35. Cunnane G, Fitzgerald O, Beeton C, Cawston TE, Bresnihan B. Early joint erosions and serum levels of matrix metalloproteinase 1, matrix metalloproteinase 3, and tissue inhibitor of metalloproteinases 1 in rheumatoid arthritis. Arthritis Rheum 2001;44: 2263–74.

36. Benito MJ, Murphy E, Murphy EP, van den Berg WB, FitzGerald O, Bresnihan B. Increased synovial tissue NF-kappa B1 expression at sites adjacent to the cartilage-pannus junction in rheumatoid arthritis. Arthritis Rheum 2004; 50: 1781-7.

37. Ambartsumian N, Klingelhofer J, Grigorian M, et al. The metastasis-associated Mts1(S100A4) protein could act as an angiogenic factor. Oncogene 2001; 20: 4685–95.

38. Grigorian MS, Tulchinsky EM, Zain S, et al. The mts1 gene and control of tumor metastasis. Gene 1993;135:229–38.

39. Kato C, Kojima T, Komaki M, et al. S100A4 inhibition by RNAi up-regulates osteoblast related genes in periodontal ligament cells. Biochem Biophys Res Commun 2005; 326: 147–53.

Literatura autora

a) Šenolt L, Braun M, Olejárová M, Forejtová Š, Gatterová J, Pavelka K. Increased pentosidine, an Advanced Glycation Endproduct, in serum and synovial fluid from patients with knee osteoarthritis and its relation with cartilage oligomeric matrix protein. Ann Rheum Dis 2005; 64: 886–90.

b) Pavelka K, Forejtova S, Olejarova M, Gatterova J, Senolt L, Spacek P, Braun M, Hulejova M, Stovickova J, Pavelkova A. Hyaluronic acid levels may have predictive value for the progression of knee osteoarthritis. Osteoarthritis Cartilage 2004; 12: 277–83.

c) Šenolt L, Gatterová J, Pavelka K. Oligomerní protein chrupavkové matrix (COMP) v séru a synovialní tekutině u pacientů s revmatoidní artritidou a osteoartrózou 2005; Rheumatologia 2005; 19: 123–128.

d) Vilím V, Vobůrka Z, Vytášek R, Šenolt L, Tchetverikov I, Kraus VB, Pavelka K. Monoclonal antibodies to human cartilage oligomeric matrix protein: epitope mapping and characterization of sandwich ELISA. Clin chim acta 2003; 328: 59–69.

e) Šenolt L, Grigorian M, Lukanidin E, Michel BA, Gay RE, Gay S, Pavelka K, Neidhart M. S100A4 (Mts1): is there any relation to the pathogenesis of rheumatoid arthritis? Autoimmun Rev 2006; 5: 129–31.

f) Šenolt L, Grigorian M, Lukanidin E, Simmen B, Michel BA, Pavelka K, Gay RE, Gay S, Neidhart M. S100A4 is expressed at site of invasion in rheumatoid arthritis synovium and modulates production of matrix metalloproteinases. Ann Rheum Dis 2006; v tisku

Další práce autora

1. Forejtová Š, Pavelka K, Gatterová J, Šenolt L. Rychle progredující osteoartróza a metody hodnocení progrese osteoartrózy. Čes Revmatol 2002; 1: 11–18.

2. Šenolt L, Braun M, Pavelka K. Konečné produkty pokročilé glykace u pacientů s osteoartrózou a revmatoidní artritidou a jejich potenciální úloha v patogenezi těchto onemocnění. Čes Revmatol 2003; 3: 146–56.

3. Šenolt L, Pavelka K. Oxid dusnatý (NO), intermediární produkty NO a jejich vliv na patogenezi osteoartrózy. Čes Revmatol 2003; 1: 42–50.

4. Olejárová M, Seidl Z, Vaněčková M, Gatterová J, Forejtová Š, Šenolt L, Pavelka K. Longitudinální sledování progrese MR obrazu kolenních kloubů u gonartrózy. Výsledky dvouleté studie. Čes Revmatol 2003; 4: 169–73.

5. Šenolt L, Pavelka K. Význam subchondrální kosti v patogenezi osteoartrózy. Osteologický Bulletin 2004; 9: 54–58.

6. Šenolt L, Vencovský J, Pavelka K. Transdukční signální dráhy – cíl terapie revmatoidní artritidy budoucnosti? Čes. Revmatol 2005; 2: 58–66.

7. Šenolt L, Pavelka K. Molecular markers of osteoarthritis. Acta Chir Orthop Traumatol Cech 2005; 72: 191–6.

7. Šenolt L. Význam synoviálních fibroblastů v patogenezi revmatoidní artritidy. Čes Revmatol 2006; 2: 65–70.

Dermatology & STDs Paediatric rheumatology Rheumatology
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