Skip to main content
Top
Published in: Rheumatology International 7/2008

01-05-2008 | Original Article

The imbalance between osteoprotegerin and cathepsin K in the serum of patients with longstanding rheumatoid arthritis

Authors: Martin Skoumal, Günther Haberhauer, Gernot Kolarz, Gerhard Hawa, Wolfgang Woloszczuk, Anton Klingler, Franz Varga, Klaus Klaushofer

Published in: Rheumatology International | Issue 7/2008

Login to get access

Abstract

Osteoprotegerin (OPG) and soluble receptor activator of NF-kappa B ligand (sRANKL) together regulate the bone metabolism among other cytokines, whereby cathepsin K has a potent collagen-degrading activity. An imbalance of this system may be partly responsible for the skeletal complications of RA. Expanding on a previous study, we investigated the relationship between OPG, sRANKL and cathepsin K levels in the serum of patients with longstanding RA. We measured serum levels of OPG, sRANKL and cathepsin K of 100 patients with active, longstanding RA. We detected elevated serum levels of cathepsin K (median 54.8 pmol/l) and OPG (median 4.8 pmol/l), but normal sRANKL levels (median 0.2 pmol/l). Cathepsin K did not show a correlation with the overexpressed OPG (P = 0.64) and sRANKL (P = 0.81). The radiological destruction correlates significantly with cathepsin K (P = 0.004) and OPG (P = 0.007). We speculate that the increased levels of OPG are effective in compensating the action of sRANKL, but do not directly prevent bone degradation, as reflected by the elevated serum levels of cathepsin K.
Literature
1.
go back to reference Haynes DR, Barg E, Crotti TN, Holding C, Weedon H et al (2003) Osteoprotegerin expression in synovial tissue from patients with rheumatoid arthritis, spondylarthropathies and osteoarthritis and normal controls. Rheumatology 42:123–34PubMedCrossRef Haynes DR, Barg E, Crotti TN, Holding C, Weedon H et al (2003) Osteoprotegerin expression in synovial tissue from patients with rheumatoid arthritis, spondylarthropathies and osteoarthritis and normal controls. Rheumatology 42:123–34PubMedCrossRef
2.
go back to reference Crotti TN, Smith MD, Weedon H, Ahern MJ, Findlay DM, Kraan M et al (2002) Receptor activator NF-kappa B ligand (RANKL) expression in synovial tissue from patients with rheumatoid arthritis, spondylarthropathy, osteoarthritis, and from normal patients: semiquantitative and quantitative analysis. Ann Rheum Dis 61:1047–1054PubMedCrossRef Crotti TN, Smith MD, Weedon H, Ahern MJ, Findlay DM, Kraan M et al (2002) Receptor activator NF-kappa B ligand (RANKL) expression in synovial tissue from patients with rheumatoid arthritis, spondylarthropathy, osteoarthritis, and from normal patients: semiquantitative and quantitative analysis. Ann Rheum Dis 61:1047–1054PubMedCrossRef
3.
go back to reference Hou WS, Li Z, Keyszer G, Weber E, Levy R, Klein MJ, Gravallese EM, Goldring SR, Bromme D (2002) Comparison of cathepsin K and S expression within the rheumatoid and osteoarthritic synovium. Arthritis Rheum 46(3):663–674PubMedCrossRef Hou WS, Li Z, Keyszer G, Weber E, Levy R, Klein MJ, Gravallese EM, Goldring SR, Bromme D (2002) Comparison of cathepsin K and S expression within the rheumatoid and osteoarthritic synovium. Arthritis Rheum 46(3):663–674PubMedCrossRef
4.
go back to reference Kaneko M, Tomita T, Nakase T, Ohsawa Y, Seki H, Takeuchi E, Takano H, Shi K, Takahi K, Kominami E, Uchiyama Y, Yoshikawa H, Ochi T (2001) Expression of proteinases and inflammatory cytokines in subchondral bone regions in the destructive joint of rheumatoid arthritis. Rheumatology (Oxford) 40(3):247–255CrossRef Kaneko M, Tomita T, Nakase T, Ohsawa Y, Seki H, Takeuchi E, Takano H, Shi K, Takahi K, Kominami E, Uchiyama Y, Yoshikawa H, Ochi T (2001) Expression of proteinases and inflammatory cytokines in subchondral bone regions in the destructive joint of rheumatoid arthritis. Rheumatology (Oxford) 40(3):247–255CrossRef
5.
go back to reference Skoumal M, Kolarz G, Woloszczuk W, Hawa G, Klingler A (2005) Serum cathepsin K levels of patients with destructive rheumatoid arthritis: correlation with radiological destruction. Arthritis Res Ther 7:R65–R70PubMedCrossRef Skoumal M, Kolarz G, Woloszczuk W, Hawa G, Klingler A (2005) Serum cathepsin K levels of patients with destructive rheumatoid arthritis: correlation with radiological destruction. Arthritis Res Ther 7:R65–R70PubMedCrossRef
6.
go back to reference Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, Healey LA, Kaplan SR, Liang MH (1988) The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 31:315–324PubMedCrossRef Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, Healey LA, Kaplan SR, Liang MH (1988) The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 31:315–324PubMedCrossRef
7.
go back to reference Ritchie DM, Boyle JA, McInnes JM, Jasani MK, Dalakos TG, Grieveson P (1968) Clinical studies with an articular index for the assessments of joint tenderness in patients with rheumatoid arthritis. Q J Med 147:393–406 Ritchie DM, Boyle JA, McInnes JM, Jasani MK, Dalakos TG, Grieveson P (1968) Clinical studies with an articular index for the assessments of joint tenderness in patients with rheumatoid arthritis. Q J Med 147:393–406
8.
go back to reference Smolen JS, Breedveld FC, Eberl G (1995) Validity and reliability of the twenty-eight-joint count for the assessment of rheumatoid arthritis. Arthritis Rheum 38:38–43PubMedCrossRef Smolen JS, Breedveld FC, Eberl G (1995) Validity and reliability of the twenty-eight-joint count for the assessment of rheumatoid arthritis. Arthritis Rheum 38:38–43PubMedCrossRef
9.
go back to reference Larsen A, Dale K, Eek M (1976) Radiographic evaluation of rheumatoid arthritis and related conditions by standard reference films. Acta Radiol Diagn 18:481–491 Larsen A, Dale K, Eek M (1976) Radiographic evaluation of rheumatoid arthritis and related conditions by standard reference films. Acta Radiol Diagn 18:481–491
10.
go back to reference Kudlacek S, Schneider P, Pietschmann P, Woloszczuk W, Willvonseder R (2003) Serum levels of osteoprotegerin increase with age in a healthy adult population. Bone 32:681–686PubMedCrossRef Kudlacek S, Schneider P, Pietschmann P, Woloszczuk W, Willvonseder R (2003) Serum levels of osteoprotegerin increase with age in a healthy adult population. Bone 32:681–686PubMedCrossRef
11.
go back to reference Hawa G, Brinskelle-Schmal N, Glatz K, Maitzen S, WoloszczukW (2003) Immunoassay for soluble RANKL (receptor activator of NF-κB ligand) in serum. Clin Lab 49(9–10):461–463PubMed Hawa G, Brinskelle-Schmal N, Glatz K, Maitzen S, WoloszczukW (2003) Immunoassay for soluble RANKL (receptor activator of NF-κB ligand) in serum. Clin Lab 49(9–10):461–463PubMed
12.
go back to reference Skoumal M, Kolarz G, Woloszczuk W, Hawa G, Klingler A (2004) Serum osteoprotegerin but not receptor activator of NF-kappa B ligand correlates with the Larsen score in rheumatoid arthritis. Ann Rheum Dis 63(2):216–217PubMedCrossRef Skoumal M, Kolarz G, Woloszczuk W, Hawa G, Klingler A (2004) Serum osteoprotegerin but not receptor activator of NF-kappa B ligand correlates with the Larsen score in rheumatoid arthritis. Ann Rheum Dis 63(2):216–217PubMedCrossRef
13.
go back to reference Schett G, Redlich K, Smolen JS (2003) The role of osteoprotegerin in arthritis. Arthritis Res Ther 5:239–245PubMedCrossRef Schett G, Redlich K, Smolen JS (2003) The role of osteoprotegerin in arthritis. Arthritis Res Ther 5:239–245PubMedCrossRef
14.
go back to reference Collin-Osdoby P, Rothe L, Anderson F, Nelson M, Maloney W, Osdoby P (2001) Receptor activator of NF-kappa B and osteoprotegerin expression by human microvascular endothelial cells, regulation by inflammatory cytokines, and role in human osteoclastogenesis. J Biol Chem 276:20659–20672PubMedCrossRef Collin-Osdoby P, Rothe L, Anderson F, Nelson M, Maloney W, Osdoby P (2001) Receptor activator of NF-kappa B and osteoprotegerin expression by human microvascular endothelial cells, regulation by inflammatory cytokines, and role in human osteoclastogenesis. J Biol Chem 276:20659–20672PubMedCrossRef
15.
go back to reference Jones DH, Kong YY, Penninger JM (2002) Role of RANKL and RANK in bone loss and arthritis. Ann Rheum Dis 61(Suppl II):ii32–ii39PubMed Jones DH, Kong YY, Penninger JM (2002) Role of RANKL and RANK in bone loss and arthritis. Ann Rheum Dis 61(Suppl II):ii32–ii39PubMed
16.
go back to reference Li J, Sarosi I, Yan XQ, Morony S, Capparelli C, Tan HL, McCabe S (1997) RANK is the intrinsinc hematopoietic cell surface receptor that controls osteoclastogenesis and regulation of bone mass and calcium metabolism. Proc Natl Acad Sci USA 97(4):1566–1571CrossRef Li J, Sarosi I, Yan XQ, Morony S, Capparelli C, Tan HL, McCabe S (1997) RANK is the intrinsinc hematopoietic cell surface receptor that controls osteoclastogenesis and regulation of bone mass and calcium metabolism. Proc Natl Acad Sci USA 97(4):1566–1571CrossRef
17.
go back to reference Kong YY, Yoshida H, Sarosi I, Tan HL, Timms E, Capparelli C, Morony S, Oliveira-dos-Santos AJ, Van G, Itie A, Khoo W, Wakeham A, Dunstan CR, Lacey DL, Mak TW, Boyle WJ, Penninger JM (1999) OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature 397:315–323PubMedCrossRef Kong YY, Yoshida H, Sarosi I, Tan HL, Timms E, Capparelli C, Morony S, Oliveira-dos-Santos AJ, Van G, Itie A, Khoo W, Wakeham A, Dunstan CR, Lacey DL, Mak TW, Boyle WJ, Penninger JM (1999) OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature 397:315–323PubMedCrossRef
18.
go back to reference Komuro H, Olee T, Kuhn K, Quach J, Brinson DC, Shikhman A, Valbracht J, Creighton-Achermann L, Lotz M (2001) The osteoprotegerin/receptor activator of nuclear factor kappa B/receptor activator of nuclear factor kappa B ligand system in cartilage. Arthritis Rheum 44:2768–2776PubMedCrossRef Komuro H, Olee T, Kuhn K, Quach J, Brinson DC, Shikhman A, Valbracht J, Creighton-Achermann L, Lotz M (2001) The osteoprotegerin/receptor activator of nuclear factor kappa B/receptor activator of nuclear factor kappa B ligand system in cartilage. Arthritis Rheum 44:2768–2776PubMedCrossRef
19.
go back to reference Ziolkowska M, Kurowska M, Radzikowska A, Luszczykiewicz G, Wieland P, Dziewczopolski W, Filipowicz-Sosnowska A, Pazdur J, Szechinski J, Kowalczewski J, Rell-Bakalarska M, Maslinski W (2002) High levels of osteoprotegerin and soluble receptor activator of nuclear factor kappa B ligand in serum of rheumatoid arthritis patients and their normalization after anti-tumor necrosis factor alpha treatment. Arthritis Rheum 46(7):1744–1753PubMedCrossRef Ziolkowska M, Kurowska M, Radzikowska A, Luszczykiewicz G, Wieland P, Dziewczopolski W, Filipowicz-Sosnowska A, Pazdur J, Szechinski J, Kowalczewski J, Rell-Bakalarska M, Maslinski W (2002) High levels of osteoprotegerin and soluble receptor activator of nuclear factor kappa B ligand in serum of rheumatoid arthritis patients and their normalization after anti-tumor necrosis factor alpha treatment. Arthritis Rheum 46(7):1744–1753PubMedCrossRef
20.
go back to reference Marotte H, Maslinski W, Miossec P (2005) Circulating tumor necrosis factor-alpha bioactivity in rheumatoid arthritis patients treated with Infliximab: link to clinical response. Arthritis Res Ther 7:R149–R155PubMedCrossRef Marotte H, Maslinski W, Miossec P (2005) Circulating tumor necrosis factor-alpha bioactivity in rheumatoid arthritis patients treated with Infliximab: link to clinical response. Arthritis Res Ther 7:R149–R155PubMedCrossRef
21.
go back to reference Haynes DR, Crotti TN, Loric M, Bain GI, Atkins GJ, Findlay DM (2001) Osteoprotegerin and receptor activator of nuclear factor-(B ligand (RANKL) regulate osteoclast formation by cells in the human rheumatoid arthritic joint. Rheumatology 40:623–630PubMedCrossRef Haynes DR, Crotti TN, Loric M, Bain GI, Atkins GJ, Findlay DM (2001) Osteoprotegerin and receptor activator of nuclear factor-(B ligand (RANKL) regulate osteoclast formation by cells in the human rheumatoid arthritic joint. Rheumatology 40:623–630PubMedCrossRef
22.
go back to reference Hofbauer LC, Heufelder AC (2001) Role of receptor activator of nuclear factor-(B ligand and osteoprotegerin in bone cell biology. J Mol Med 79:243–253PubMedCrossRef Hofbauer LC, Heufelder AC (2001) Role of receptor activator of nuclear factor-(B ligand and osteoprotegerin in bone cell biology. J Mol Med 79:243–253PubMedCrossRef
23.
go back to reference Wittrant Y, Couillaud S, Theoleyre S, Dunstan C, Heymann D, Redini F (2002) Osteoprotegerin differentially regulates protease expression in osteoclast cultures. Biochem Biophys Res Commun 293(1):38–44PubMedCrossRef Wittrant Y, Couillaud S, Theoleyre S, Dunstan C, Heymann D, Redini F (2002) Osteoprotegerin differentially regulates protease expression in osteoclast cultures. Biochem Biophys Res Commun 293(1):38–44PubMedCrossRef
24.
go back to reference Troen BR (2004) The role of cathepsin K in normal bone resorption. Drug News Perspect 17(1):19–28PubMedCrossRef Troen BR (2004) The role of cathepsin K in normal bone resorption. Drug News Perspect 17(1):19–28PubMedCrossRef
25.
go back to reference Hou WS, Li Z, Buttner FH, Bartnik E, Bromme D (2003) Cleavage site specifity of cathepsin K toward cartilage proteoglycans and protease complex formation. Biol Chem 384(6):691–697CrossRef Hou WS, Li Z, Buttner FH, Bartnik E, Bromme D (2003) Cleavage site specifity of cathepsin K toward cartilage proteoglycans and protease complex formation. Biol Chem 384(6):691–697CrossRef
26.
go back to reference Hummel KM, Petrow PK, Franz JK, Maller-Ladner U, Aicher WK, Gay RE, Brämme D, Gay S (1998) Cysteine protease cathepsin K mRNA is expressed in synovium of patients with rheumatoid arthritis and is detected at sites of synovial bone destruction. J Rheumatol 25(10):1887–1894PubMed Hummel KM, Petrow PK, Franz JK, Maller-Ladner U, Aicher WK, Gay RE, Brämme D, Gay S (1998) Cysteine protease cathepsin K mRNA is expressed in synovium of patients with rheumatoid arthritis and is detected at sites of synovial bone destruction. J Rheumatol 25(10):1887–1894PubMed
27.
go back to reference Votta BJ, Levy MA, Badger A, Bradbeer J, Dodds RA, James IE, Thompson S, Bossaard MJ, Carr T, Connor JR, Tomaszek TA, Szewczuk L, Drake FH, Veber DF, Gowen M (1997) Peptide aldehyde inhibitor of cathepsin K inhibit bone resorption both in vitro and in vivo. J Bone Miner Res 12(9):1396–1406PubMedCrossRef Votta BJ, Levy MA, Badger A, Bradbeer J, Dodds RA, James IE, Thompson S, Bossaard MJ, Carr T, Connor JR, Tomaszek TA, Szewczuk L, Drake FH, Veber DF, Gowen M (1997) Peptide aldehyde inhibitor of cathepsin K inhibit bone resorption both in vitro and in vivo. J Bone Miner Res 12(9):1396–1406PubMedCrossRef
28.
go back to reference Tavares FX, Boncek V, Deaton DN, Hassell AM, Long ST, Miller AB, Payne AA, Miller LR, Shewchuk LM, Wells-Knecht K, Willard DH, Wright LL, Zhou HQ (2004) Design of potent, selective and orally bioavailable inhibitors of cysteine protease cathepsin K. J Med Chem 47(3):588–599PubMedCrossRef Tavares FX, Boncek V, Deaton DN, Hassell AM, Long ST, Miller AB, Payne AA, Miller LR, Shewchuk LM, Wells-Knecht K, Willard DH, Wright LL, Zhou HQ (2004) Design of potent, selective and orally bioavailable inhibitors of cysteine protease cathepsin K. J Med Chem 47(3):588–599PubMedCrossRef
29.
go back to reference Skoumal M, Kolarz G, Haberhauer G, Woloszczuk W, Hawa G, Klingler A (2005) Osteoprotegerin and the receptor activator of NF-kappa B ligand in the serum and synovial fluid. A comparison of patients with longstanding rheumatoid arthritis and osteoarthritis. Rheumatol Int 26(1):63–69PubMedCrossRef Skoumal M, Kolarz G, Haberhauer G, Woloszczuk W, Hawa G, Klingler A (2005) Osteoprotegerin and the receptor activator of NF-kappa B ligand in the serum and synovial fluid. A comparison of patients with longstanding rheumatoid arthritis and osteoarthritis. Rheumatol Int 26(1):63–69PubMedCrossRef
Metadata
Title
The imbalance between osteoprotegerin and cathepsin K in the serum of patients with longstanding rheumatoid arthritis
Authors
Martin Skoumal
Günther Haberhauer
Gernot Kolarz
Gerhard Hawa
Wolfgang Woloszczuk
Anton Klingler
Franz Varga
Klaus Klaushofer
Publication date
01-05-2008
Publisher
Springer-Verlag
Published in
Rheumatology International / Issue 7/2008
Print ISSN: 0172-8172
Electronic ISSN: 1437-160X
DOI
https://doi.org/10.1007/s00296-007-0506-3

Other articles of this Issue 7/2008

Rheumatology International 7/2008 Go to the issue
Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Watch this official video from ACC.24. Dr. Biykem Bozkurt discuss last year's major advances in heart failure and cardiomyopathies.