- Email: [email protected]
Identification, validation and qualification of biomarkers for osteoarthritis in humans and companion animals: Mission for the next decade
The Veterinary Journal 185 (2010) 95–97
Contents lists available at ScienceDirect
The Veterinary Journal journal homepage: www.elsevier.com/locate/tvjl
Personal View
Identification, validation and qualification of biomarkers for osteoarthritis in humans and companion animals: Mission for the next decade Ali Mobasheri a,*, Yves Henrotin b a Musculoskeletal Research Group, Division of Veterinary Medicine, School of Veterinary Medicine and Science, Faculty of Medicine and Health Sciences, University of Nottingham Sutton Bonington Campus, Leicestershire, UK b Bone and Cartilage Research Unit, University of Liège, Institute of Pathology, Sart-Tilman, 4000 Liège, Belgium
Articular cartilage is an avascular, aneural and alymphatic connective tissue designed to distribute mechanical load and provide a wear-resistance surface to articulating joints (Buckwalter and Mankin, 1998). The tissue is made up of a tough and mechanically resilient extracellular matrix (ECM) consisting mainly of the cartilage-specific type II collagen (approximately 85–90% of the total collagen content) and aggregating proteoglycans (predominantly aggrecan) that occupies more than 90% of the total volume of the tissue (Carney and Muir, 1988; Muir, 1995). The chondrocyte is the only cell type that resides within cartilage and is solely responsible for the synthesis and turnover of the ECM (Archer and Francis-West, 2003). Despite its durability, cartilage has a very limited self-maintaining capability and is vulnerable to mechanical injury and prone to structural damage and degradation. Osteoarthritis (OA) is one of the most common forms of arthritis affecting synovial joints in humans and companion animals, namely, the horse, dog and cat. It is estimated that at least 80% of cases of lameness and joint diseases in companion animals are classified as OA (Lees, 2003). OA is known by several other names, including degenerative joint disease (DJD), osteoarthrosis, hypertrophic arthritis and degenerative arthritis.1,2 In humans, joint inflammation and the degeneration of articular cartilage are integral components of the clinical syndrome of OA, which is one of the most common causes of pain and disability in the ageing population (Buckwalter and Mankin, 1998). There is a strong correlation between increasing age and the prevalence of OA and recent evidence of age-related changes in the function of chondrocytes, suggest that such changes in articular cartilage contribute to the development and progression of OA (Buckwalter et al., 2000, 2005). In some of the literature, OA has been incorrectly described as ‘idiopathic’. In reality, it is a progressive disorder characterised by destruction of articular cartilage and subchondral bone and by synovial changes. Synovial inflammation or synovitis is a frequently observed phenomenon in OA joints and contributes to disease pathogenesis through formation of various catabolic and pro-inflammatory mediators altering the balance of cartilage matrix degradation and repair (Sutton et al., 2009).
* Corresponding author. Tel.: +44 115 951 6449; fax: +44 115 951 6440. E-mail address: [email protected] (A. Mobasheri). 1 See: http://www.arthritis.org/disease-center.php?disease_id = 32. 2 See: http://www.nlm.nih.gov/medlineplus/osteoarthritis.html. 1090-0233/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.tvjl.2010.05.026
Several drug classes are available for treating musculoskeletal disease in companion animals; these include non-steroidal antiinflammatory drugs (NSAIDs) and corticosteroids. The management of OA in pets is largely palliative, focusing on the alleviation of symptoms, mainly pain. The most appropriate first line treatment is the use of mild analgesia. The next escalation of treatment consists of the lowest effective dose of NSAIDs for the shortest period of time. When other pharmacological agents have been ineffective (or are contraindicated) the use of weak opioids may be considered for the treatment of refractory pain in canine patients with limb OA. For refractory cases, full dose NSAIDs along with local intra-articular injections of glucocorticoids or hyaluronic acid supplementation may be used while awaiting assessment of suitability for joint replacement. Glucosamine sulfate/hydrochloride and chondroitin sulfate may provide symptomatic benefit, but if no response is apparent within 6 months of treatments, they should be discontinued according to the guidelines provided by ACR,3 EULAR4 and OARSI.5 No current pharmacotherapy can be considered to be an approved structural/disease modifying therapy for OA. A recent systematic review of the literature has provided evidence for the efficacy of NSAIDs, supporting longer-term use of these agents for increased clinical effect (Innes et al., 2010). However, the long-term use of NSAIDs is highly controversial, especially in view of the adverse gastrointestinal side effects of many of these substances. Complementary therapies such as oral nutraceuticals and dietary supplements, used in conjunction with NSAIDs, may offer significant benefits to companion animals with joint disorders such as OA (Goggs et al., 2005; Henrotin et al., 2005). Although NSAIDs and nutraceuticals may slow down the pace of disease progression they cannot stop or reverse the cartilage degradation and synovial inflammation that occurs in OA. There are currently no drugs on the market capable of protecting articular cartilage from further damage or affect the pathways of disease progression. Recent disappointments in late-stage clinical development of disease-modifying osteoarthritic drugs (DMOADs) have refocused efforts on OA biomarker discovery. The field of OA biomarkers is rapidly expanding. Biomarker discovery and validation for OA has
3 4 5
The American College of Radiology; see: www.acr.org. The European League Against Rheumatism; see: www.eular.org. The Osteoarthritis Research Society International; see: www.oarsi.org.
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A. Mobasheri, Y. Henrotin / The Veterinary Journal 185 (2010) 95–97
accelerated significantly as we have increased our understanding of joint tissue molecules and their complex interactions (Kraus, 2005). One of the main issues responsible for driving this agenda has been the acute need for improved OA outcome measures in clinical trials (Kraus, 2005; Hunter et al., 2010). The diagnosis of OA is generally based on clinical and radiographic changes, which occur fairly late and have poor sensitivity for monitoring disease progression (Rousseau and Delmas, 2007). Currently, the assessment of the inter-bone distance and loss of joint space on a radiograph of the affected joint remains the ‘gold standard’. Unfortunately, the limitations of joint space narrowing as an outcome are considerable and have hampered the qualification of biomarkers as a surrogate endpoint in drug discovery. We need to identify biomarkers that may be useful for characterising the burden of the disease, diagnosis, prognosis and efficacy of treatment in OA. Current research in this area is aimed at developing an analytical toolbox with the potential to improve the clinical development process (Qvist et al., 2010). It has been suggested that combining existing biomarkers may improve their prognostic accuracy and help identify at-risk patients (Williams, 2009). The challenge now is to identify sensitive and reliable biomarkers that can be accurately measured in blood or urine. This is especially critical in the early phases of disease so that these treatments can be started as soon as possible to slow down progression of the disease. Several such biomarkers of OA already exist. The earliest ones to be identified were the ‘neo-epitopes’ created by enzymatic degradation of collagen type II by matrix metalloproteinases (reviewed by Lohmander (2004)). The best-known examples of this are the type II collagen C-telopeptide fragments (CTX-II) (Christgau et al., 2001; Poole et al., 2004) the cleavage neo-epitope (C-2-C) and the denaturation epitope (Coll2-1) and its nitrated form Coll21NO2. Coll2-1NO2 can be considered as an indicator of the oxidative related type II collagen network degradation (Henrotin et al., 2007). There are also non-collagenous biomarkers of cartilage degradation. The most promising so far is cartilage oligomeric matrix protein (COMP), which has shown promise as a diagnostic and prognostic indicator and as a marker of the disease severity and the effect of treatment (Jordan, 2004; Tseng et al., 2009). Another interesting candidate is YKL-40, which may provide a snapshot of catabolic events in joint tissues, potentially allowing rapid assessment of pharmacotherapy (Huang and Wu, 2009). In a recent Special Issue of The Veterinary Journal Dr. Elaine Garvican and her colleagues review the literature and discuss biomarkers of cartilage turnover in two separate articles (Garvican et al., 2010a,b). The first review sets the scene by describing the need for accurate and reliable information about collagen turnover before outlining the molecular processes by which the so-called ‘neo-epitopes’ are generated by the action of matrix metalloproteinases (Garvican et al., 2010a). The authors considered the application of ‘neo-epitopes’ as biomarkers for studying healthy and diseased cartilage with particular emphasis on veterinary species. The second review focused on non-collagenous and non-proteoglycan components of cartilage (Garvican et al., 2010b). These molecules can also be detected following their release from cartilage ECM as a result of altered turnover in OA. The authors addressed recent post-genomic strategies that have been used to distinguish populations with OA from normal populations. This second article describes the application of a metabolomic fingerprint of OA and summarises some of the techniques that can be used to measure the concentrations of some of non-collagenous biomarkers in joint disease. These two reviews provide the readers of The Veterinary Journal with an up-to-date summary of the research progress in the area of OA biomarkers in companion animals. We would like to offer a few cautionary notes to readers. In biomarker research it is usually the very low abundance proteins that are the interesting ones – unusual or apparently irrelevant proteins
that may transiently appear or disappear. The ideal biomarkers for OA are unlikely to be the fragments or degraded forms of essential ECM proteins. By the time the major collagenous and non-collagenous components of the ECM are detectable in urine, blood or synovial fluid too much damage and inflammation has already occurred in the synovial joint. Although systemic (serum or urine) biomarkers offer a potential alternative method of quantifying total body burden of disease, no OA-related biomarker has ever been stringently qualified (Kraus et al., 2010). Serum proteins and acute phase proteins (APPs) have also been proposed as disease biomarkers (Sipe, 1995). However, these are unlikely to be clinically useful biomarkers for OA, not least as there are numerous APPs that vary widely in disease states and there is considerable debate as to which ones actually participate in disease processes. The abundance of APPs and their non-specific upregulation in response to inflammatory diseases means that they cannot (by definition) be used as OA biomarkers. Nevertheless, the future is bright for OA research and efforts in this area may well identify panels of biomarkers that may be used as noninvasive and reliable diagnostic and prognostic indicators of disease severity and response to pharmacotherapy.
References Archer, C.W., Francis-West, P., 2003. The chondrocyte. International Journal of Biochemistry and Cell Biology 35, 401–404. Buckwalter, J.A., Mankin, H.J., 1998. Articular cartilage: degeneration and osteoarthritis, repair, regeneration, and transplantation. Instructional Course Lectures 47, 487–504. Buckwalter, J.A., Martin, J., Mankin, H.J., 2000. Synovial joint degeneration and the syndrome of osteoarthritis. Instructional Course Lectures 49, 481–489. Buckwalter, J.A., Mankin, H.J., Grodzinsky, A.J., 2005. Articular cartilage and osteoarthritis. Instructional Course Lectures 54, 465–480. Carney, S.L., Muir, H., 1988. The structure and function of cartilage proteoglycans. Physiological Reviews 68, 858–910. Christgau, S., Garnero, P., Fledelius, C., Moniz, C., Ensig, M., Gineyts, E., 2001. Collagen type II C-telopeptide fragments as an index of cartilage degradation. Bone 29, 209–215. Garvican, E.R., Vaughan-Thomas, A., Innes, J.F., Clegg, P.D., 2010a. Biomarkers of cartilage turnover. Part 1: markers of collagen degradation and synthesis. The Veterinary Journal 185, 36–42. Garvican, E.R., Vaughan-Thomas, A., Clegg, P.D., Innes, J.F., 2010b. Biomarkers of cartilage turnover. Part 2: non-collagenous markers. The Veterinary Journal 185, 43–49. Goggs, R., Vaughan-Thomas, A., Clegg, P.D., Carter, S.D., Innes, J.F., Mobasheri, A., Shakibaei, M., Schwab, W., Bondy, C.A., 2005. Nutraceutical therapies for degenerative joint diseases: a critical review. Critical Reviews in Food Science and Nutrition 45, 145–164. Henrotin, Y., Sanchez, C., Balligand, M., 2005. Pharmaceutical and nutraceutical management of canine osteoarthritis: present and future perspectives. The Veterinary Journal 170, 113–123. Henrotin, Y., Addison, S., Kraus, V., Deberg, M., 2007. Type II collagen markers in osteoarthritis: what do they indicate? Current Opinion in Rheumatology 19, 444–450. Huang, K., Wu, L.D., 2009. YKL-40: a potential biomarker for osteoarthritis. Journal of International Medical Research 37, 18–24. Hunter, D.J., Losina, E., Guermazi, A., Burstein, D., Lassere, M.N., Kraus, V., 2010. A pathway and approach to biomarker validation and qualification for osteoarthritis clinical trials. Current Drug Targets 11, 536–545. Innes, J.F., Clayton, J., Lascelles, B.D., 2010. Review of the safety and efficacy of longterm NSAID use in the treatment of canine osteoarthritis. Veterinary Record 166, 226–230. Jordan, J.M., 2004. Cartilage oligomeric matrix protein as a marker of osteoarthritis. Journal of Rheumatology 70, 45–49. Kraus, V.B., 2005. Biomarkers in osteoarthritis. Current Opinion in Rheumatology 17, 641–646. Kraus, V.B., Kepler, T.B., Stabler, T., Renner, J., Jordan, J., 2010. First qualification study of serum biomarkers as indicators of total body burden of osteoarthritis. Public Library of Science One 5, e9739. Lees, P., 2003. Pharmacology of drugs used to treat osteoarthritis in veterinary practice. Inflammopharmacology 11, 385–399. Lohmander, L.S., 2004. Markers of altered metabolism in osteoarthritis. Journal of Rheumatology 70 (Suppl.), 28–35. Muir, H., 1995. The chondrocyte, architect of cartilage. Biomechanics, structure, function and molecular biology of cartilage matrix macromolecules. BioEssays 17, 1039–1048. Poole, A.R., Ionescu, M., Fitzcharles, M.A., Billinghurst, R.C., 2004. The assessment of cartilage degradation in vivo: development of an immunoassay for the
A. Mobasheri, Y. Henrotin / The Veterinary Journal 185 (2010) 95–97 measurement in body fluids of type II collagen cleaved by collagenases. Journal of Immunological Methods 294, 145–153. Qvist, P., Christiansen, C., Karsdal, M.A., Madsen, S.H., Sondergaard, B.C., Bay-Jensen, A.C., 2010. Application of biochemical markers in development of drugs for treatment of osteoarthritis. Biomarkers 15, 1–19. Rousseau, J.C., Delmas, P.D., 2007. Biological markers in osteoarthritis. Nature Clinical Practice Rheumatology 3, 346–356. Sipe, J.D., 1995. Acute-phase proteins in osteoarthritis. Seminars in Arthritis Rheumatism 25, 75–86.
97
Sutton, S., Clutterbuck, A., Harris, P., Gent, T., Freeman, S., Foster, N., Barrett-Jolley, R., Mobasheri, A., 2009. The contribution of the synovium, synovial derived inflammatory cytokines and neuropeptides to the pathogenesis of osteoarthritis. The Veterinary Journal 179, 10–24. Tseng, S., Reddi, A.H., Di Cesare, P.E., 2009. Cartilage oligomeric matrix protein (COMP): a biomarker of arthritis. Biomarker Insights 4, 33–44. Williams, F.M., 2009. Biomarkers: in combination they may do better. Arthritis Research and Therapy 11, 130.
Contents lists available at ScienceDirect
The Veterinary Journal journal homepage: www.elsevier.com/locate/tvjl
Personal View
Identification, validation and qualification of biomarkers for osteoarthritis in humans and companion animals: Mission for the next decade Ali Mobasheri a,*, Yves Henrotin b a Musculoskeletal Research Group, Division of Veterinary Medicine, School of Veterinary Medicine and Science, Faculty of Medicine and Health Sciences, University of Nottingham Sutton Bonington Campus, Leicestershire, UK b Bone and Cartilage Research Unit, University of Liège, Institute of Pathology, Sart-Tilman, 4000 Liège, Belgium
Articular cartilage is an avascular, aneural and alymphatic connective tissue designed to distribute mechanical load and provide a wear-resistance surface to articulating joints (Buckwalter and Mankin, 1998). The tissue is made up of a tough and mechanically resilient extracellular matrix (ECM) consisting mainly of the cartilage-specific type II collagen (approximately 85–90% of the total collagen content) and aggregating proteoglycans (predominantly aggrecan) that occupies more than 90% of the total volume of the tissue (Carney and Muir, 1988; Muir, 1995). The chondrocyte is the only cell type that resides within cartilage and is solely responsible for the synthesis and turnover of the ECM (Archer and Francis-West, 2003). Despite its durability, cartilage has a very limited self-maintaining capability and is vulnerable to mechanical injury and prone to structural damage and degradation. Osteoarthritis (OA) is one of the most common forms of arthritis affecting synovial joints in humans and companion animals, namely, the horse, dog and cat. It is estimated that at least 80% of cases of lameness and joint diseases in companion animals are classified as OA (Lees, 2003). OA is known by several other names, including degenerative joint disease (DJD), osteoarthrosis, hypertrophic arthritis and degenerative arthritis.1,2 In humans, joint inflammation and the degeneration of articular cartilage are integral components of the clinical syndrome of OA, which is one of the most common causes of pain and disability in the ageing population (Buckwalter and Mankin, 1998). There is a strong correlation between increasing age and the prevalence of OA and recent evidence of age-related changes in the function of chondrocytes, suggest that such changes in articular cartilage contribute to the development and progression of OA (Buckwalter et al., 2000, 2005). In some of the literature, OA has been incorrectly described as ‘idiopathic’. In reality, it is a progressive disorder characterised by destruction of articular cartilage and subchondral bone and by synovial changes. Synovial inflammation or synovitis is a frequently observed phenomenon in OA joints and contributes to disease pathogenesis through formation of various catabolic and pro-inflammatory mediators altering the balance of cartilage matrix degradation and repair (Sutton et al., 2009).
* Corresponding author. Tel.: +44 115 951 6449; fax: +44 115 951 6440. E-mail address: [email protected] (A. Mobasheri). 1 See: http://www.arthritis.org/disease-center.php?disease_id = 32. 2 See: http://www.nlm.nih.gov/medlineplus/osteoarthritis.html. 1090-0233/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.tvjl.2010.05.026
Several drug classes are available for treating musculoskeletal disease in companion animals; these include non-steroidal antiinflammatory drugs (NSAIDs) and corticosteroids. The management of OA in pets is largely palliative, focusing on the alleviation of symptoms, mainly pain. The most appropriate first line treatment is the use of mild analgesia. The next escalation of treatment consists of the lowest effective dose of NSAIDs for the shortest period of time. When other pharmacological agents have been ineffective (or are contraindicated) the use of weak opioids may be considered for the treatment of refractory pain in canine patients with limb OA. For refractory cases, full dose NSAIDs along with local intra-articular injections of glucocorticoids or hyaluronic acid supplementation may be used while awaiting assessment of suitability for joint replacement. Glucosamine sulfate/hydrochloride and chondroitin sulfate may provide symptomatic benefit, but if no response is apparent within 6 months of treatments, they should be discontinued according to the guidelines provided by ACR,3 EULAR4 and OARSI.5 No current pharmacotherapy can be considered to be an approved structural/disease modifying therapy for OA. A recent systematic review of the literature has provided evidence for the efficacy of NSAIDs, supporting longer-term use of these agents for increased clinical effect (Innes et al., 2010). However, the long-term use of NSAIDs is highly controversial, especially in view of the adverse gastrointestinal side effects of many of these substances. Complementary therapies such as oral nutraceuticals and dietary supplements, used in conjunction with NSAIDs, may offer significant benefits to companion animals with joint disorders such as OA (Goggs et al., 2005; Henrotin et al., 2005). Although NSAIDs and nutraceuticals may slow down the pace of disease progression they cannot stop or reverse the cartilage degradation and synovial inflammation that occurs in OA. There are currently no drugs on the market capable of protecting articular cartilage from further damage or affect the pathways of disease progression. Recent disappointments in late-stage clinical development of disease-modifying osteoarthritic drugs (DMOADs) have refocused efforts on OA biomarker discovery. The field of OA biomarkers is rapidly expanding. Biomarker discovery and validation for OA has
3 4 5
The American College of Radiology; see: www.acr.org. The European League Against Rheumatism; see: www.eular.org. The Osteoarthritis Research Society International; see: www.oarsi.org.
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A. Mobasheri, Y. Henrotin / The Veterinary Journal 185 (2010) 95–97
accelerated significantly as we have increased our understanding of joint tissue molecules and their complex interactions (Kraus, 2005). One of the main issues responsible for driving this agenda has been the acute need for improved OA outcome measures in clinical trials (Kraus, 2005; Hunter et al., 2010). The diagnosis of OA is generally based on clinical and radiographic changes, which occur fairly late and have poor sensitivity for monitoring disease progression (Rousseau and Delmas, 2007). Currently, the assessment of the inter-bone distance and loss of joint space on a radiograph of the affected joint remains the ‘gold standard’. Unfortunately, the limitations of joint space narrowing as an outcome are considerable and have hampered the qualification of biomarkers as a surrogate endpoint in drug discovery. We need to identify biomarkers that may be useful for characterising the burden of the disease, diagnosis, prognosis and efficacy of treatment in OA. Current research in this area is aimed at developing an analytical toolbox with the potential to improve the clinical development process (Qvist et al., 2010). It has been suggested that combining existing biomarkers may improve their prognostic accuracy and help identify at-risk patients (Williams, 2009). The challenge now is to identify sensitive and reliable biomarkers that can be accurately measured in blood or urine. This is especially critical in the early phases of disease so that these treatments can be started as soon as possible to slow down progression of the disease. Several such biomarkers of OA already exist. The earliest ones to be identified were the ‘neo-epitopes’ created by enzymatic degradation of collagen type II by matrix metalloproteinases (reviewed by Lohmander (2004)). The best-known examples of this are the type II collagen C-telopeptide fragments (CTX-II) (Christgau et al., 2001; Poole et al., 2004) the cleavage neo-epitope (C-2-C) and the denaturation epitope (Coll2-1) and its nitrated form Coll21NO2. Coll2-1NO2 can be considered as an indicator of the oxidative related type II collagen network degradation (Henrotin et al., 2007). There are also non-collagenous biomarkers of cartilage degradation. The most promising so far is cartilage oligomeric matrix protein (COMP), which has shown promise as a diagnostic and prognostic indicator and as a marker of the disease severity and the effect of treatment (Jordan, 2004; Tseng et al., 2009). Another interesting candidate is YKL-40, which may provide a snapshot of catabolic events in joint tissues, potentially allowing rapid assessment of pharmacotherapy (Huang and Wu, 2009). In a recent Special Issue of The Veterinary Journal Dr. Elaine Garvican and her colleagues review the literature and discuss biomarkers of cartilage turnover in two separate articles (Garvican et al., 2010a,b). The first review sets the scene by describing the need for accurate and reliable information about collagen turnover before outlining the molecular processes by which the so-called ‘neo-epitopes’ are generated by the action of matrix metalloproteinases (Garvican et al., 2010a). The authors considered the application of ‘neo-epitopes’ as biomarkers for studying healthy and diseased cartilage with particular emphasis on veterinary species. The second review focused on non-collagenous and non-proteoglycan components of cartilage (Garvican et al., 2010b). These molecules can also be detected following their release from cartilage ECM as a result of altered turnover in OA. The authors addressed recent post-genomic strategies that have been used to distinguish populations with OA from normal populations. This second article describes the application of a metabolomic fingerprint of OA and summarises some of the techniques that can be used to measure the concentrations of some of non-collagenous biomarkers in joint disease. These two reviews provide the readers of The Veterinary Journal with an up-to-date summary of the research progress in the area of OA biomarkers in companion animals. We would like to offer a few cautionary notes to readers. In biomarker research it is usually the very low abundance proteins that are the interesting ones – unusual or apparently irrelevant proteins
that may transiently appear or disappear. The ideal biomarkers for OA are unlikely to be the fragments or degraded forms of essential ECM proteins. By the time the major collagenous and non-collagenous components of the ECM are detectable in urine, blood or synovial fluid too much damage and inflammation has already occurred in the synovial joint. Although systemic (serum or urine) biomarkers offer a potential alternative method of quantifying total body burden of disease, no OA-related biomarker has ever been stringently qualified (Kraus et al., 2010). Serum proteins and acute phase proteins (APPs) have also been proposed as disease biomarkers (Sipe, 1995). However, these are unlikely to be clinically useful biomarkers for OA, not least as there are numerous APPs that vary widely in disease states and there is considerable debate as to which ones actually participate in disease processes. The abundance of APPs and their non-specific upregulation in response to inflammatory diseases means that they cannot (by definition) be used as OA biomarkers. Nevertheless, the future is bright for OA research and efforts in this area may well identify panels of biomarkers that may be used as noninvasive and reliable diagnostic and prognostic indicators of disease severity and response to pharmacotherapy.
References Archer, C.W., Francis-West, P., 2003. The chondrocyte. International Journal of Biochemistry and Cell Biology 35, 401–404. Buckwalter, J.A., Mankin, H.J., 1998. Articular cartilage: degeneration and osteoarthritis, repair, regeneration, and transplantation. Instructional Course Lectures 47, 487–504. Buckwalter, J.A., Martin, J., Mankin, H.J., 2000. Synovial joint degeneration and the syndrome of osteoarthritis. Instructional Course Lectures 49, 481–489. Buckwalter, J.A., Mankin, H.J., Grodzinsky, A.J., 2005. Articular cartilage and osteoarthritis. Instructional Course Lectures 54, 465–480. Carney, S.L., Muir, H., 1988. The structure and function of cartilage proteoglycans. Physiological Reviews 68, 858–910. Christgau, S., Garnero, P., Fledelius, C., Moniz, C., Ensig, M., Gineyts, E., 2001. Collagen type II C-telopeptide fragments as an index of cartilage degradation. Bone 29, 209–215. Garvican, E.R., Vaughan-Thomas, A., Innes, J.F., Clegg, P.D., 2010a. Biomarkers of cartilage turnover. Part 1: markers of collagen degradation and synthesis. The Veterinary Journal 185, 36–42. Garvican, E.R., Vaughan-Thomas, A., Clegg, P.D., Innes, J.F., 2010b. Biomarkers of cartilage turnover. Part 2: non-collagenous markers. The Veterinary Journal 185, 43–49. Goggs, R., Vaughan-Thomas, A., Clegg, P.D., Carter, S.D., Innes, J.F., Mobasheri, A., Shakibaei, M., Schwab, W., Bondy, C.A., 2005. Nutraceutical therapies for degenerative joint diseases: a critical review. Critical Reviews in Food Science and Nutrition 45, 145–164. Henrotin, Y., Sanchez, C., Balligand, M., 2005. Pharmaceutical and nutraceutical management of canine osteoarthritis: present and future perspectives. The Veterinary Journal 170, 113–123. Henrotin, Y., Addison, S., Kraus, V., Deberg, M., 2007. Type II collagen markers in osteoarthritis: what do they indicate? Current Opinion in Rheumatology 19, 444–450. Huang, K., Wu, L.D., 2009. YKL-40: a potential biomarker for osteoarthritis. Journal of International Medical Research 37, 18–24. Hunter, D.J., Losina, E., Guermazi, A., Burstein, D., Lassere, M.N., Kraus, V., 2010. A pathway and approach to biomarker validation and qualification for osteoarthritis clinical trials. Current Drug Targets 11, 536–545. Innes, J.F., Clayton, J., Lascelles, B.D., 2010. Review of the safety and efficacy of longterm NSAID use in the treatment of canine osteoarthritis. Veterinary Record 166, 226–230. Jordan, J.M., 2004. Cartilage oligomeric matrix protein as a marker of osteoarthritis. Journal of Rheumatology 70, 45–49. Kraus, V.B., 2005. Biomarkers in osteoarthritis. Current Opinion in Rheumatology 17, 641–646. Kraus, V.B., Kepler, T.B., Stabler, T., Renner, J., Jordan, J., 2010. First qualification study of serum biomarkers as indicators of total body burden of osteoarthritis. Public Library of Science One 5, e9739. Lees, P., 2003. Pharmacology of drugs used to treat osteoarthritis in veterinary practice. Inflammopharmacology 11, 385–399. Lohmander, L.S., 2004. Markers of altered metabolism in osteoarthritis. Journal of Rheumatology 70 (Suppl.), 28–35. Muir, H., 1995. The chondrocyte, architect of cartilage. Biomechanics, structure, function and molecular biology of cartilage matrix macromolecules. BioEssays 17, 1039–1048. Poole, A.R., Ionescu, M., Fitzcharles, M.A., Billinghurst, R.C., 2004. The assessment of cartilage degradation in vivo: development of an immunoassay for the
A. Mobasheri, Y. Henrotin / The Veterinary Journal 185 (2010) 95–97 measurement in body fluids of type II collagen cleaved by collagenases. Journal of Immunological Methods 294, 145–153. Qvist, P., Christiansen, C., Karsdal, M.A., Madsen, S.H., Sondergaard, B.C., Bay-Jensen, A.C., 2010. Application of biochemical markers in development of drugs for treatment of osteoarthritis. Biomarkers 15, 1–19. Rousseau, J.C., Delmas, P.D., 2007. Biological markers in osteoarthritis. Nature Clinical Practice Rheumatology 3, 346–356. Sipe, J.D., 1995. Acute-phase proteins in osteoarthritis. Seminars in Arthritis Rheumatism 25, 75–86.
97
Sutton, S., Clutterbuck, A., Harris, P., Gent, T., Freeman, S., Foster, N., Barrett-Jolley, R., Mobasheri, A., 2009. The contribution of the synovium, synovial derived inflammatory cytokines and neuropeptides to the pathogenesis of osteoarthritis. The Veterinary Journal 179, 10–24. Tseng, S., Reddi, A.H., Di Cesare, P.E., 2009. Cartilage oligomeric matrix protein (COMP): a biomarker of arthritis. Biomarker Insights 4, 33–44. Williams, F.M., 2009. Biomarkers: in combination they may do better. Arthritis Research and Therapy 11, 130.