Rheumatology, Osteoarthritis
12. May 2020
Characterization of the interleukin-17 Effect on Articular Cartilage in a Translational Model: An Explorative Study
Background: Osteoarthritis (OA) is a progressive, chronic disease characterized by articular cartilage destruction. The pro-inflammatory cytokine IL-17 levels have been reported elevated in serum and synovial fluid of OA patients and correlated with increased cartilage defects and bone remodeling. T…
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Journal:
Authors:
- Sinkeviciute D,
- Aspberg A,
- He Y,
- Bay-Jensen AC,
- Önnerfjord P,
Rheumatology, Osteoarthritis, Extracellular Matrix Research
7. Apr 2020
Sprifermin (rhFGF18) Versus Vehicle Induces a Biphasic Process of Extracellular Matrix Remodeling in Human Knee OA Articular Cartilage Ex Vivo
Sprifermin, recombinant human fibroblast growth factor 18 (rhFGF18), induces cartilage regeneration in knees of patients with osteoarthritis (OA). We hypothesized that a temporal multiphasic process of extracellular matrix (ECM) degradation and formation underlie this effect. We aimed to characteriz…
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Journal:
Authors:
- Reker D,
- Siebuhr AS,
- Thudium CS,
- Gantzel T,
- Ladel C,
- Michaelis M,
- Aspberg A,
- Berchtold MW,
- Karsdal MA,
- Gigout A,
- Bay-Jensen AC,
Rheumatology, Osteoarthritis
15. Mar 2020
Clinical and Biochemical Factors Associated With Risk of Total Joint Replacement and Radiographic Progression in Osteoarthritis: Data From Two Phase III Clinical Trials
Objectives: Clinical trials of new disease-modifying treatments for osteoarthritis should demonstrate a positive effect on a functional outcome or reduction in joint failure in order to be considered successful. Total joint replacement (TJR) surgery may be considered as joint failure, but great vari…
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Journal:
Authors:
- Bihlet A,
- Bjerre-Bastos JJ,
- Andersen JR,
- Byrjalsen I,
- Karsdal MA,
- Bay-Jensen AC,
Rheumatology, Osteoarthritis, Extracellular Matrix Research
14. Nov 2019
Inflammation and joint destruction may be linked to the generation of cartilage metabolites of ADAMTS-5 through activation of toll-like receptors.
OBJECTIVE:
Links between pain and joint degradation are poorly understood. We investigated the role of activation of Toll-like receptors (TLR) by cartilage metabolites in initiating and maintaining the inflammatory loop in OA causing joint destruction.
METHODS:
Synovial membrane explants (SMEs)…
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Journal:
Authors:
- Sharma N,
- drobinski P,
- Kayed A,
- Chen Z,
- Kjelgaard-Petersen CF,
- Gantzel T,
- Karsdal MA,
- Michaels M,
- Ladel C,
- Bay-Jensen AC,
- Lindemann S,
- Thudium CS,
Rheumatology, Bone, Osteoporosis, Osteoarthritis, Biomarker position
30. Sep 2019
Biochemical markers in osteoarthritis with lessons learned from osteoporosis.
Osteoarthritis (OA) is a disease of the whole joint, including synovium, bone and cartilage. OA is a slow degenerative and very heterogeneous disease, with both varying levels of disease activity and progression. Biomarkers are urgently needed to assist drug developers in selecting and developing th…
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Authors:
Rheumatology, Osteoarthritis, Biomarker position, Bone
3. Sep 2019
Associations between biomarkers of bone and cartilage turnover, gender, pain categories and radiographic severity in knee osteoarthritis.
BACKGROUND:
Excessive cartilage degradation is a known characteristic of osteoarthritis (OA). Biochemical markers, such as uCTX-II, have been shown to be associated with disease severity, yet the tissue origin of CTX-II has been disputed. This analysis investigates the association between OA knee j…
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Journal:
Authors:
- Bihlet AR,
- Byrjalsen I,
- Bay-Jensen AC,
- Andersen JR,
- Christiansen C,
- Riis BJ,
- Karsdal MA,
Rheumatology, Osteoarthritis, Rheumatoid Arthritis
24. Jul 2019
Identification of pathological RA endotypes using blood-based biomarkers reflecting tissue metabolism. A retrospective and explorative analysis of two phase III RA studies.
There is an increasing demand for accurate endotyping of patients according to their pathogenesis to allow more targeted treatment. We explore a combination of blood-based joint tissue metabolites (neoepitopes) to enable patient clustering through distinct disease profiles. We analysed data from two…
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Journal:
Authors:
- Blair JPM,
- Bager C,
- Karsdal MA,
- Bay-Jensen AC,
Rheumatology, Osteoarthritis
26. Jun 2019
Incidence of total hip and total knee replacements from the prospective epidemiologic risk factor study: considerations for event driven clinical trial design
BACKGROUND:
Osteoarthritis (OA) leads to joint failure and total joint replacement (TJR, either hip (H) or knee (K)). Worsening of pain and joint space narrowing are believed to be surrogates for joint failure; however, we hypothesize that TJR, as a reflection of joint failure, can be used as an en…
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Authors:
Rheumatology, Osteoarthritis
31. Jan 2019
Molecular taxonomy of osteoarthritis for patient stratification, disease management and drug development
PURPOSE OF REVIEW:
This review focuses on the molecular taxonomy of osteoarthritis from the perspective of molecular biomarkers. We discuss how wet biochemical markers may be used to understand disease pathogenesis and progression and define molecular endotypes of osteoarthritis and how these corre…
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Journal:
Authors:
- mobasheri A,
- Van Spil WE,
- Budd E,
- Uzieliene I,
- Bernotiene E,
- Bay-Jensen AC,
- Larkin J,
- Levesque MC,
- Gualillo O,
- Henrotin Y,
Rheumatology, Osteoarthritis, Rheumatoid Arthritis
14. Jan 2019
Potential diagnostic value of a type X collagen neo-epitope biomarker for knee osteoarthritis.
OBJECTIVE:
Phenotypic changes of chondrocytes toward hypertrophy might be fundamental in the pathogenesis of OA, of which type X collagen (Col10) is a well-known marker. The purpose was to develop a specific immunoassay for blood quantification of a newly identified neo-epitope of type X collagen t…
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Journal:
Authors:
- He Y,
- Manon-Jensen T,
- Arendt-Nielsen L,
- Petersen KK,
- Christiansen T,
- Samuels J,
- Abramson S,
- Karsdal MA,
- Attur M,
- Bay-Jensen AC,
Rheumatology, Osteoarthritis
18. Dec 2018
Serological biomarker profiles of rapidly progressive osteoarthritis in tanezumab-treated patients.
There is a need for efficacious and safe pain treatments for OA (osteoarthritis). The nerve growth factor (NGF) antibody tanezumab is associated with high efficacy, but when combined with chronic NSAID treatment shows an increased risk of rapidly progressive osteoarthritis (RPOA) in a small group of…
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Journal:
Authors:
- Karsdal MA,
- Verburg KM,
- West CR,
- Bay-Jensen AC,
- Keller DS,
- Arends RHGP,
Rheumatology, Osteoarthritis
6. Nov 2018
A Novel High Sensitivity Type II Collagen Blood-Based Biomarker, PRO-C2, for Assessment of Cartilage Formation
N-terminal propeptide of type II collagen (PIINP) is a biomarker reflecting cartilage formation. PIINP exists in two main splice variants termed as type IIA and type IIB collagen NH₂-propeptide (PIIANP, PIIBNP). PIIANP has been widely recognized as a cartilage formation biomarker. However, the utili…
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Journal:
Authors:
- Luo Y,
- He Y,
- Gudmann NS,
- Henriksen K,
- Simonsen O,
- Ladel C,
- Michaels M,
- Mobasheri A,
- Karsdal MA,
- Bay-Jensen AC,
Rheumatology, Osteoarthritis
7. Sep 2018
IL-37 diminishes proteoglycan loiss in human OA cartilage: donor-specific link between IL-37 and MMP-3.
OBJECTIVE:
A hallmark of osteoarthritis (OA) is degradation of articular cartilage proteoglycans. In isolated human OA chondrocytes, the anti-inflammatory cytokine Interleukin-37 (IL-37) lowers the expression of the proteolytic MMP and ADAMTS enzymes, which mediate this degradation. Therefore, we i…
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Journal:
Authors:
- Van Geffen EW,
- Van Caam APM,
- Van de Loo FA,
- Van Lent PLEM,
- Koenders MI,
- Thudium CS,
- Bay-Jensen AC,
- Blaney Davidson EN,
- Van der Kraan PM,
Rheumatology, Osteoarthritis
29. Jul 2018
Tofacitinib and TPCA-1 Exert Chondroprotective Effects on Extracellular Matrix Turnover in Bovine Articular Cartilage Ex vivo.
OBJECTIVE:
Currently, there are no disease-modifying osteoarthritis drugs (DMOADs) approved for osteoarthritis. It is hypothesized that a subtype of OA may be driven by inflammation and may benefit from treatment with anti-inflammatory small molecule inhibitors adopted from treatments of rheumatoid…
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Journal:
Authors:
- Kjelgaard-Petersen CF,
- Sharma N,
- Kayed A,
- Karsdal MA,
- Mobasheri A,
- Hägglund P,
- Bay-Jensen AC,
- Thudium CS,
Rheumatology, Osteoarthritis
25. Apr 2018
Protein biomarkers associated with pain mechanisms in osteoarthritis
Osteoarthritis (OA) is the most common arthritic disease in the world, leading to debilitating pain and destruction of joint tissues. While pain is the hallmark symptom of osteoarthritis, clear associations between pain and disease processes involved in joint deterioration are lacking. OA pain is mu…
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Journal:
Authors:
- Thudium CS,
- Löfvall H,
- Karsdal MA,
- Bay-Jensen AC,
- Bihlet A,
Rheumatology, Osteoarthritis, Extracellular Matrix Research
25. Apr 2018
Aggrecanase degradation of type III collagen is associated with clinical knee pain
There is a lack of biochemical markers for non-invasive and objective assessment of symptomatic osteoarthritis (OA). Aggrecanase activity has been shown to be associated with joint deterioration and symptomatic disease through the degradation of extracellular matrix proteins, such as type III collag…
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Journal:
Authors:
- Bay-Jensen AC,
- Kjelgaard-Petersen CF,
- Petersen KK,
- Arendt-Nielsen L,
- Quasnichka HL,
- Mobasheri A,
- Karsdal MA,
- Leeming DJ,
Osteoarthritis
17. Jan 2018
Identification of pain categories associated with change in pain in patients receiving placebo: Data from Two Phase 3 Randomized Clinical Trials in Symptomatic Knee Osteoarthritis
BACKGROUND:
Pain is the principal clinical symptom of osteoarthritis (OA), and development of safe and effective analgesics for OA pain is needed. Drug development of new analgesics for OA pain is impaired by substantial change in pain in patients receiving placebo, and more data describing clinica…
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Journal:
Authors:
- Bihlet AR,
- Byrjalsen I,
- Bay-Jensen AC,
- Andersen JR,
- Christiansen C,
- Riis BJ,
- Valter I,
- Karsdal MA,
- Hochberg MC,
Rheumatology, Osteoarthritis
12. Dec 2017
Sprifermin (rhFGF18) Modulates Extracellular Matrix Turnover in Cartilage Explants ex vivo
BACKGROUND:
Sprifermin (recombinant human fibroblast growth factor 18) is in clinical development as a potential disease-modifying osteoarthritis drug (DMOAD). In vitro studies have shown that cartilage regenerative properties of sprifermin involve chondrocyte proliferation and extracellular matrix…
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Journal:
Authors:
- Reker D,
- Kjelgaard-Petersen CF,
- Siebuhr AS,
- Michaelis M,
- Gigout A,
- Karsdal MA,
- Ladel C,
- Bay-Jensen AC,
Rheumatology, Osteoarthritis
16. Oct 2017
Development and use of biochemical markers in osteoarthritis: current update
PURPOSE OF REVIEW:
There is an increasing demand for noninvasive and descriptive biochemical markers (biomarkers) in osteoarthritis; for enabling early drug development (including translational research), evaluating clinical trial at an early stage and for subtyping. Purpose of the review is to rev…
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Journal:
Authors:
- Bay-Jensen AC,
- Thudium CS,
- Mobasheri A,
Rheumatology, Osteoarthritis
14. Oct 2017
Biochemical marker discovery, testing and evaluation for facilitating OA drug discovery and development
Osteoarthritis (OA) is the most common form of joint disease. This presents the OA research community and pharmaceutical companies developing disease-modifying OA drugs (DMOADs) with great opportunities. The different OA subtypes complicate the traditional approaches for developing new treatments. I…
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Journal:
Authors:
- Bay-Jensen AC,
- Thudium CS,
- Mobasheri A,
- Gualillo O,
Rheumatology, Osteoarthritis, Obesity
9. Sep 2017
A machine learning approach for the identification of new biomarkers for knee osteoarthritis development in overweight and obese women
OBJECTIVE:
Knee osteoarthritis (OA) is among the higher contributors to global disability. Despite its high prevalence, currently, there is no cure for this disease. Furthermore, the available diagnostic approaches have large precision errors and low sensitivity. Therefore, there is a need for new …
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Journal:
Authors:
- Bacardit J,
- Henrotin Y,
- Bierma-Zeinstra SMA,
- Thudium CS,
- Bay-Jensen AC,
- Runhaar J,
- Lazzarini N,
Rheumatology, Osteoarthritis
18. Aug 2017
Sprifermin (rhFGF18) enables proliferation of chondrocytes producing a hyaline cartilage matrix
OBJECTIVE:
Fibroblast growth factor (FGF) 18 has been shown to increase cartilage volume when injected intra-articularly in animal models of osteoarthritis (OA) and in patients with knee OA (during clinical development of the recombinant human FGF18, sprifermin). However, the exact nature of this e…
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Journal:
Authors:
- Gigout A,
- Guehring H,
- Froemel D,
- Meurer A,
- Ladel C,
- Reker D,
- Bay-Jensen AC,
- Karsdal MA,
- Lindemann S,
Obesity, Rheumatology, Osteoarthritis
27. Jul 2017
Effects of dietary weight loss with and without exercise on interstitial matrix turnover and tissue inflammation biomarkers in adults with knee osteoarthritis: the Intensive Diet and Exercise for Arthritis trial (IDEA)
OBJECTIVE:
To examine the effects of dietary weight loss, with and without exercise, on selected soluble biomarkers in overweight and obese older adults with symptomatic knee osteoarthritis (OA).
DESIGN:
Blood samples were analyzed from 429 participants in the Intensive Diet and Exercise for Ar…
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Journal:
Authors:
- Loeser RF,
- Beavers DP,
- Bay-Jensen AC,
- Karsdal MA,
- Nicklas BJ,
- Guermazi A,
- Hunter DJ,
- Messier SP,
Extracellular Matrix Research, Osteoarthritis
22. Mar 2017
Biomarker of extracellular matrix remodelling C1M and proinflammatory cytokine IL-6 are related to synovitis and pain in endstage knee osteoarthritis patients
Little is known about local and systemic biomarkers in relation to synovitis and pain in end-stage osteoarthritis (OA) patients. We investigated the associations between the novel extracellular matrix biomarker, C1M, and local and systemic interleukin 6 (IL-6) with synovitis and pain. Serum C1M, pla…
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Journal:
Authors:
- Radojcic MR,
- Thudium CS,
- Henriksen K,
- Tan K,
- Karlsten R,
- Dudley A,
- Chessell I,
- Karsdal MA,
- Bay-Jensen AC,
- Arbit E,
- Guermazi A,
Osteoarthritis, Rheumatology, Extracellular Matrix Research
20. Feb 2017
Chondrocyte secretome: a source of novel insights and exploratory biomarkers of osteoarthritis
The extracellular matrix (ECM) of articular cartilage is comprised of complex networks of proteins and glycoproteins, all of which are expressed by its resident cell, the chondrocyte. Cartilage is a unique tissue given its complexity and ability to resist repeated load and deformation. The mechanism…
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Journal:
Authors:
- Sanchez C,
- Bay-Jensen AC,
- Pap T,
- Dvir-Ginzberg M,
- Quasnichka H,
- Barrett-Jolley R,
- Mobasheri A,
- Henrotin Y,
Osteoarthritis
20. Jan 2017
Identification of serological biomarker profiles associated with total joint replacement in osteoarthritis patients
OBJECTIVE:
Establish a biomarker panel associated with all-cause total joint replacement (TJR) through identification of patients with osteoarthritis (OA) who do or do not progress to TJR and investigate effects of nonsteroidal anti-inflammatory drugs (NSAIDs).
DESIGN:
Serum samples from patien…
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Journal:
Authors:
- Arends RH,
- Karsdal MA,
- Verburg KM,
- West CR,
- Bay-Jensen AC,
- Keller DS,
Rheumatology, Osteoarthritis
16. Jan 2017
Osteoarthritis Year in Review 2016: biomarkers (biochemical markers)
PURPOSE:
The aim of this "Year in Review" article is to summarize and discuss the implications of biochemical marker related articles published between the Osteoarthritis Research Society International (OARSI) 2015 Congress in Seattle and the OARSI 2016 Congress in Amsterdam.
METHODS:
The PubMe…
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Journal:
Authors:
- Mobasheri A,
- Bay-Jensen AC,
- Van Spil WE,
- Larkin J,
- Levesque MC,
Rheumatology, Osteoarthritis
2. Aug 2016
Disease-modifying treatments for osteoarthritis (DMOADs) of the knee and hip: lessons learned from failures and opportunities for the future
Osteoarthritis (OA) is the biggest unmet medical need among the many musculoskeletal conditions and the most common form of arthritis. It is a major cause of disability and impaired quality of life in the elderly. We review several ambitious but failed attempts to develop joint structure-modifying t…
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Journal:
Authors:
- Karsdal MA,
- Michaelis M,
- Ladel C,
- Siebuhr AS,
- Bihlet AR,
- Andersen JR,
- Guehring H,
- Christiansen C,
- Bay-Jensen AC,
- Kraus VB,
Rheumatology, Osteoarthritis
5. May 2016
The Need for Predictive, Prognostic, Objective and Complementary Blood-Based Biomarkers in Osteoarthritis (OA)
Osteoarthritis (OA) has traditionally been viewed as a non-inflammatory arthropathy and has not been considered a ‘serious disease’. However, this view has radically changed in recent years, due to the complexity and heterogeneity of the patient populations, spiralling socio-economical costs and lon…
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Journal:
Authors:
- Bay-Jensen AC,
- Henrotin Y,
- Karsdal MA,
- Mobasheri A,
Rheumatology, Osteoarthritis
28. Apr 2016
Osteoarthritis biomarkers derived from cartilage extracellular matrix: Current status and future perspectives
Specific soluble biomarkers can be powerful tools for the diagnosis, prognosis and personalized management of osteoarthritis (OA). Biomarkers are potential indicators of the effect of a drug on cartilage metabolism and provide crucial information about the mechanisms of drug action. In this review, …
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Journal:
Authors:
- Henrotin Y,
- Sanchez C,
- Bay-Jensen AC,
- Mobasheri A,
Rheumatology, Osteoarthritis
1. Apr 2016
Association between biomarkers of tissue inflammation and progression of osteoarthritis: evidence from the Rotterdam study cohort
BACKGROUND:
We aimed to investigate the prognostic value of two biomarkers of tissue inflammation, matrix metalloproteinase-dependent degradation of C-reactive protein (CRPM) and connective tissue type I collagen turnover (C1M), on the incidence and progression of radiographic osteoarthritis (OA) i…
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Journal:
Authors:
- Saberi Hosnijeh F,
- Siebuhr AS,
- Uitterlinden AG,
- Oei EH,
- Hofman A,
- Karsdal MA,
- Bierma-Zeinstra SM,
- Bay-Jensen AC,
- van Meurs JB,
Rheumatology, Osteoarthritis, Extracellular Matrix Research
10. Feb 2016
Synovitis biomarkers: ex vivo characterization of three biomarkers for identification of inflammatory osteoarthritis
OBJECTIVE:
Characterize biomarkers measuring extracellular matrix turnover of inflamed osteoarthritis synovium.
METHODS:
Human primary fibroblast-like synoviocytes and synovial membrane explants (SMEs) treated with various cytokines and growth factors were assessed by C1M, C3M, and acMMP3 in …
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Journal:
Authors:
- Bay-Jensen AC,
- Karsdal MA,
- Ladel C,
- Christiansen TG,
- Siebuhr AS,
- Kjelgaard-Petersen CF,
Rheumatology, Osteoarthritis
25. Jan 2016
Osteoarthritis year in review 2015: soluble biomarkers and the BIPED criteria
OBJECTIVE:
To review and summarize biomarker data published from April 2014 to May 2015 to provide insight to the ongoing work in the field of osteoarthritis (OA). Furthermore, to summarize the BIPED criteria and set it in context of the medical needs of 2015.
METHODS:
PubMed was used as search…
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Journal:
Authors:
- Bay-Jensen AC,
- Reker D,
- Kjelgaard-Petersen CF,
- Mobasheri A,
- Karsdal MA,
- Ladel C,
- Henrotin Y,
- Thudium CS,
Rheumatology, Osteoarthritis
21. Dec 2015
Serum cartilage oligomeric matrix protein and development of radiographic and painful knee osteoarthritis. A community-based cohort of middle-aged women
CONTEXT AND OBJECTIVE:
We evaluated the predictive value of serum cartilage oligomeric matrix protein (sCOMP) levels over 20 years on the development of radiographic (RKOA) and painful knee osteoarthritis (KOA) in a longitudinal cohort of middle-aged women.
MATERIALS AND METHODS:
Five hundred a…
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Journal:
Authors:
- Kluzek S,
- Bay-Jensen AC,
- Judge A,
- Karsdal MA,
- Shorthose M,
- Spector T,
- Hart D,
- Newton JL,
- Arden NK,
Rheumatology, Osteoarthritis
2. Dec 2015
Sensitization and Serological Biomarkers in Knee Osteoarthritis Patients With Different Degrees of Synovitis
OBJECTIVE:
Synovitis is a frequent condition in knee osteoarthritis (KOA) and has been associated with pain. This study investigated the links between the pressure hyperalgesia, the clinical pain, the degree of the synovitis, inflammatory biomarkers, and tissue-specific biomarkers in KOA patients.
…
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Journal:
Authors:
- Petersen KK,
- Siebuhr AS,
- Graven-Nielsen T,
- Simonsen O,
- Boesen MP,
- Gudbergsen H,
- Karsdal MA,
- Bay-Jensen AC,
- Arendt-Nielsen L,
Rheumatology, Osteoarthritis
20. Oct 2015
Inflammation (or synovitis)-driven osteoarthritis: an opportunity for personalizing prognosis and treatment?
The disabling and painful disease osteoarthritis (OA) is the most common form of arthritis. Strong evidence suggests that a subpopulation of OA patients has a form of OA driven by inflammation. Consequently, understanding when inflammation is the driver of disease progression and which OA patients m…
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Journal:
Authors:
- Siebuhr AS,
- Bay-Jensen AC,
- Jordan JM,
- Kjelgaard-Petersen CF,
- Christiansen C,
- Abramson SB,
- Attur M,
- Berenbaum F,
- Kraus V,
- Karsdal MA,
Rheumatology, Osteoarthritis
24. Apr 2015
The effect of protease inhibitors on the induction of osteoarthritis-related biomarkers in bovine full-depth cartilage explants
OBJECTIVE:
The specific degradation of type II collagen and aggrecan by matrix metalloproteinase (MMP)-9, -13 and ADAMTS-4 and -5 (aggrecanase-1 and -2) in the cartilage matrix is a critical step in pathology of osteoarthritis (OA). The aims of this study were: i) To investigate the relative contri…
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Journal:
Authors:
- He Y,
- Zheng Q,
- Jiang M,
- Christiansen TG,
- Kassem M,
- Karsdal MA,
- Bay-Jensen AC,
Rheumatology, Osteoarthritis
1. Apr 2015
OA phenotypes, rather than disease stage, drive structural progression--identification of structural progressors from 2 phase III randomized clinical studies with symptomatic knee OA
BACKGROUND/PURPOSE:
The aim of this study was to identify key characteristics of disease progression through investigation of the association of radiographic progression over two years with baseline Joint Space Width (JSW), Kellgren-Lawrence (KL) grade, Western Ontario and McMaster Universities Art…
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Journal:
Authors:
- Karsdal MA,
- Bihlet A,
- Byrjalsen I,
- Alexandersen P,
- Ladel C,
- Michaels M,
- Andersen JR,
- Riis BJ,
- Kraus V,
- Bay-Jensen AC,
- Christiansen C,
Rheumatology, Osteoarthritis
1. Apr 2015
Treatment of symptomatic knee osteoarthritis with oral salmon calcitonin: results from two phase 3 trials
PURPOSE:
To evaluate the structure-modifying and symptom efficacy, as well as safety and tolerability of oral salmon calcitonin (sCT) formulated with a 5-CNAC carrier (a molecule based on Eligen(®) technology), in osteoarthritis (OA) patients with moderate to severe knee pain and joint structural d…
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Journal:
Authors:
- Karsdal MA,
- Byrjalsen I,
- Alexandersen P,
- Bihlet A,
- Andersen JR,
- Riis BJ,
- Bay-Jensen AC,
- Christiansen C,
- CSMC021C2301/1 investigators,
Rheumatology, Osteoarthritis
1. Jan 2015
Association between biochemical cartilage markers and clinical symptoms in patients with hip osteoarthritis: cohort study with 2-year follow-up
OBJECTIVES:
To assess associations between uCTX-II or uCIIM and severity of hip pain in patients with mild-moderate hip osteoarthritis (OA) over a 2-year period, and establish whether the level of these biomarkers at baseline could estimate a specific trajectory of hip pain.
DESIGN:
A cohort st…
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Journal:
Authors:
- Dorleijn DM,
- Luijsterburg PA,
- Bay-Jensen AC,
- Siebuhr AS,
- Karsdal MA,
- Rozendaal RM,
- Bos PK,
- Bierma-Zeinstra SM,
Rheumatology, Osteoarthritis
1. Jan 2015
Identifying specific profiles in patients with different degrees of painful knee osteoarthritis based on serological biochemical and mechanistic pain biomarkers: a diagnostic approach based on cluster analysis
Biochemical and pain biomarkers can be applied to patients with painful osteoarthritis profiles and may provide more details compared with conventional clinical tools. The aim of this study was to identify an optimal combination of biochemical and pain biomarkers for classification of patients with …
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Journal:
Authors:
- Egsgaard LL,
- Eskehave TN,
- Bay-Jensen AC,
- Hoeck HC,
- Arendt-Nielsen L,
Rheumatology, Osteoarthritis
11. Dec 2014
Association between experimental pain biomarkers and serologic markers in patients with different degrees of painful knee osteoarthritis
OBJECTIVE:
To assess the association between pain mechanisms (sensitization) and biochemical markers for cartilage, bone, and inflammation in patients with knee pain.
METHODS:
The study group comprised 281 patients with different degrees of knee pain intensity and radiographic findings (using t…
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Journal:
Authors:
- Arendt-Nielsen L,
- Eskehave TN,
- Egsgaard LL,
- Petersen KK,
- Graven-Nielsen T,
- Hoeck HC,
- Simonsen O,
- Siebuhr AS,
- Karsdal MA,
- Bay-Jensen AC,
Osteoarthritis, Rheumatology
17. Oct 2014
Cartilage turnover reflected by metabolic processing of type II collagen: a novel marker of anabolic function in chondrocytes
The aim of this study was to enable measurement of cartilage formation by a novel biomarker of type II collagen formation. The competitive enzyme-linked immunosorbent assay (ELISA) Pro-C2 was developed and characterized for assessment of the beta splice variant of type II procollagen (PIIBNP). This …
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Journal:
Authors:
- Gudmann NS,
- Wang J,
- Hoielt S,
- Chen P,
- Siebuhr AS,
- He Y,
- Christiansen TG,
- Karsdal MA,
- Bay-Jensen AC,
Osteoarthritis
1. Sep 2014
Alpha C-telopeptide of type I collagen is associated with subchondral bone turnover and predicts progression of joint space narrowing and osteophytes in osteoarthritis
OBJECTIVE:
To evaluate joint tissue remodeling using the urinary collagen biomarkers urinary α-C-telopeptide of type I collagen (α-CTX) and urinary C-telopeptide of type II collagen (CTX-II) and to determine the association of these biomarkers with osteoarthritis (OA) severity, progression, and loc…
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Journal:
Authors:
- Huebner JL,
- Bay-Jensen AC,
- Huffman K,
- He Y,
- Leeming DJ,
- McDaniel GE,
- Karsdal MA,
- Kraus VB,
Rheumatology, Osteoarthritis
28. Aug 2014
Association Between Experimental Pain Biomarkers and Serological Markers in Patients With Different Degree of Painful Knee Osteoarthritis
OBJECTIVE:
To assess the association between pain mechanisms (sensitization) and biochemical markers for cartilage, bone, and inflammation in patients with knee pain.
METHODS:
The study group comprised 281 patients with different degrees of knee pain intensity and radiographic findings (using t…
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Journal:
Authors:
- Arendt-Nielsen L,
- Eskehave TN,
- Egsgaard LL,
- Petersen KK,
- Graven-Nielsen T,
- Hoeck HC,
- Simonsen O,
- Siebuhr AS,
- Karsdal MA,
- Bay-Jensen AC,
Rheumatology, Osteoarthritis
1. Aug 2014
Biomarkers of cartilage and surrounding joint tissue
The identification and clinical demonstration of efficacy and safety of osteo- and chondro-protective drugs are met with certain difficulties. During the last few decades, the pharmaceutical industry has, in the field of rheumatology, experienced disappointments associated with the development of di…
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Journal:
Authors:
- Siebuhr AS,
- He Y,
- Gudmann NS,
- Gram A,
- Kjelgaard-Petersen CF,
- Qvist P,
- Karsdal MA,
- Bay-Jensen AC,
Rheumatology, Osteoarthritis
23. Jul 2014
Meta-analysis identifies loci affecting levels of the potential osteoarthritis biomarkers sCOMP and uCTX-II with genome wide significance
BACKGROUND:
Research for the use of biomarkers in osteoarthritis (OA) is promising, however, adequate discrimination between patients and controls may be hampered due to innate differences. We set out to identify loci influencing levels of serum cartilage oligomeric protein (sCOMP) and urinary C-te…
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Journal:
Authors:
- Ramos YF,
- Metrustry S,
- Arden NK,
- Bay-Jensen AC,
- Beekman M,
- de Craen AJ,
- Cupples LA,
- Esko T,
- Evangelou E,
- Felson DT,
- Hart DJ,
- Ioannidis JP,
- Karsdal MA,
- Kloppenburg M,
- Lafeber F,
- Metspalu A,
- Panoutsopoulou K,
- Slagboom PE,
- Spector TD,
- van Spil EW,
- Uitterlinden AG,
- Zhu Y,
- Valdes AM,
- van Meurs JB,
- Meulenbelt I,
Bone, Rheumatology, Osteoarthritis
6. Jun 2014
ALPHA-CTX is associated with subchondral bone turnover and predicts progression of joint space narrowing and osteophytes in osteoarthritis
OBJECTIVE:
To evaluate joint tissue remodeling, with urinary collagen biomarkers, uALPHA CTX and uCTXII, and their association with osteoarthritis (OA) severity, progression, and localized knee bone turnover.
METHODS:
Participants (N=149) with symptomatic and radiographic knee OA underwent fixe…
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Journal:
Authors:
- Huebner JL,
- Bay-Jensen AC,
- Huffman KM,
- He Y,
- Leeming DJ,
- McDaniel GE,
- Karsdal MA,
- Kraus VB,
Osteoarthritis
22. May 2014
Large scale meta-analysis of urinary C-terminal telopeptide, serum cartilage oligomeric protein and matrix metalloprotease degraded type II collagen and their role in prevalence, incidence and progression of osteoarthritis
OBJECTIVE:
To evaluate the role of three cartilage-derived biomarkers on osteoarthritis (OA): urinary C-terminal telopeptide (uCTX-II), serum cartilage oligomeric protein (sCOMP), and serum MMP degraded type II collagen (sC2M).
SUBJECTS AND METHODS:
Samples from 3582 individuals from the Rotter…
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Journal:
Authors:
- Valdes AM,
- Meulenbelt I,
- Chassaing E,
- Arden NK,
- Bierma-Zeinstra S,
- Hart D,
- Hofman A,
- Karsdal MA,
- Kloppenburg M,
- Kroon HM,
- Slagboom EP,
- Spector TD,
- Uitterlinden AG,
- van Meurs JB,
- Bay-Jensen AC,
Osteoarthritis
19. Mar 2014
The active form of MMP-3 is a marker of synovial inflammation and cartilage turnover in inflammatory joint diseases
BACKGROUND:
Matrix metalloproteinase-3 (MMP-3) plays an important role in the pathology of rheumatoid arthritis (RA) and ankylosing spondylitis (AS). Measurement of active MMP-3 in clinical samples could provide information about progression of rheumatoid diseases, and potentially response to treat…
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Journal:
Authors:
- Sun S,
- Bay-Jensen AC,
- Karsdal MA,
- Siebuhr AS,
- Zheng Q,
- Maksymowych WP,
- Christiansen TG,
- Henriksen K,
Rheumatology, Osteoarthritis
6. Feb 2014
The coupling of bone and cartilage turnover in osteoarthritis: opportunities for bone antiresorptives and anabolics as potential treatments?
Osteoarthritis (OA) is the most common form of arthritic disease, and a major cause of disability and impaired quality of life in the elderly. OA is a complex disease of the entire joint, affecting bone, cartilage and synovium that thereby presents multiple targets for treatment. This manuscript wil…
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Journal:
Authors:
- Karsdal MA,
- Bay-Jensen AC,
- Lories RJ,
- Abramson S,
- Spector T,
- Pastoureau P,
- Christiansen C,
- Attur M,
- Henriksen K,
- Goldring SR,
- Kraus V,
Rheumatology, Osteoarthritis
22. Jan 2014
Osteoarthritis--a case for personalized health care?
For both economic and ethical reasons, identification of the optimal treatment for each individual patient is a pressing concern, not only for the patients and their physician, but also health care payers and the pharmaceutical industry. In the field of osteoarthritis (OA) this is of particular rele…
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Journal:
Authors:
- Karsdal MA,
- Christiansen C,
- Ladel C,
- Henriksen K,
- Kraus VB,
- Bay-Jensen AC,
Rheumatology, Osteoarthritis
7. Jan 2014
Identification and characterisation of osteoarthritis patients with inflammation derived tissue turnover
OBJECTIVES:
Osteoarthritis (OA) is a degenerative disease with a subset of patients experiencing joint inflammation, but C-reactive protein (CRP) has shown limited use in OA as a diagnostic marker. The aim was to identify subpopulations of patients with high or low levels of acute (high sensitive C…
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Journal:
Authors:
- Siebuhr AS,
- Petersen KK,
- Arendt-Nielsen L,
- Egsgaard LL,
- Eskehave T,
- Christiansen C,
- Simonsen O,
- Hoeck HC,
- Karsdal MA,
- Bay-Jensen AC,
Rheumatology, Osteoarthritis
17. Oct 2013
Metabolic health in families enriched for longevity is associated with low prevalence of hand osteoarthritis and influences OA biomarker profiles
OBJECTIVES:
Individual metabolic characteristics and age-related changes may affect osteoarthritis (OA) risk as well as levels of potential OA biomarkers such as serum cartilage oligomeric protein (sCOMP) and urinary cross-linked C-telopeptide of type 2 collagen (uCTX2). We investigated hand OA and…
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Journal:
Authors:
- Bos SD,
- Beekman M,
- Maier AB,,
- Karsdal MA,
- Kwok WY,
- Bay-Jensen AC,
- Kloppenburg M,
- Slagboom PE,
- Meulenbelt I,
Rheumatology, Osteoarthritis
6. Oct 2013
The development and characterization of an ELISA specifically detecting the active form of cathepsin K
OBJECTIVE:
Cathepsin K plays essential roles in bone resorption and is intensely investigated as a therapeutic target for the treatment of osteoporosis. Hence an assessment of the active form of cathepsin K may provide important biological information in metabolic bone diseases, such as osteoporosi…
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Journal:
Authors:
- Sun S,
- Karsdal MA,
- Bay-Jensen AC,
- Sørensen MG,
- Zheng Q,
- Dziegiel MH,
- Maksymowych WP,
- Henriksen K,
Rheumatology, Osteoarthritis
14. Aug 2013
Serological identification of fast progressors of structural damage with rheumatoid arthritis
INTRODUCTION:
Rheumatoid arthritis (RA) patients with structural progression are in most need of immediate treatment to maintain tissue integrity. The serum protein fingerprint, type I collagen degradation mediated by matrix metalloproteinases (MMP)-cleavage (C1M), is a biomarker of tissue destruct…
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Journal:
Authors:
- Siebuhr AS,
- Bay-Jensen AC,
- Leeming DJ,
- Plat A,
- Byrjalsen I,
- Christiansen C,
- van de Heijde D,
- Karsdal MA,
Rheumatology, Osteoarthritis
13. May 2013
Role of hormones in cartilage and joint metabolism: understanding an unhealthy metabolic phenotype in osteoarthritis
OBJECTIVE:
Joint health is affected by local and systemic hormones. It is well accepted that systemic factors regulate the metabolism of joint tissues, and that substantial cross-talk between tissues actively contributes to homeostasis. In the current review, we try to define a subtype of osteoarth…
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Journal:
Authors:
- Bay-Jensen AC,
- Slagboom E,
- Chen-An P,
- Alexandersen P,
- Qvist P,
- Christiansen C,
- Meulenbelt I,
- Karsdal MA,
Rheumatology, Osteoarthritis
24. Apr 2013
The development and characterization of a competitive ELISA for measuring active ADAMTS-4 in a bovine cartilage ex vivo model
ADAMTS-4 (aggrecanase1) is believed to play an important role in the degradation of aggrecan during the progression of joint diseases. ADAMTS-4 is synthesized as a latent pro-enzyme that requires the removal of the pro-domain, exposing the N-terminal neoepitope, to achieve activity. We developed a m…
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Journal:
Authors:
- He Y,
- Zheng Q,
- Simonsen O,
- Petersen KK,
- Christiansen TG,
- Karsdal MA,
- Bay-Jensen AC,
Rheumatology, Osteoarthritis
14. Feb 2013
Investigation of chondrocyte hypertrophy and cartilage calcification in a full-depth articular cartilage explants model
Articular cartilage deterioration, which includes cartilage degradation and chondrocyte hypertrophy, is a hallmark of degenerative joint diseases (DJD). Chondrocyte hypertrophy is initiated in the deep layer of the cartilage; thus, a robust explants model for investigation of hypertrophy should incl…
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Journal:
Authors:
- Chen-An P,
- Andreassen KV,
- Henriksen K,
- Karsdal MA,
- Bay-Jensen AC,
Rheumatology, Osteoarthritis
3. Jan 2013
Bringing cancer serological diagnosis to a new level: focusing on HER2, protein ectodomain shedding and neoepitope technology
Cancer is a heterogeneous disease and consequently an exact diagnosis is as important as the actual therapy. Therefore, identification of novel diagnostic biomarker targets is urgently needed. Physiological and pathological changes are reflected by post-translational modifications of proteins. Each …
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Journal:
Authors:
- Wang J,
- Willumsen N,
- Zheng Q,
- Xue Y,
- Karsdal M,
- Bay-Jensen AC,
Rheumatology, Osteoarthritis
18. Dec 2012
The pathogenesis of osteoarthritis involves bone, cartilage and synovial inflammation: may estrogen be a magic bullet?
The female predominance of polyarticular osteoarthritis (OA), and in particular the marked increase of OA in women after the menopause points to a likely involvement of female sex hormones in the maintenance of cartilage homeostasis. This perception has inspired many research groups to investigate t…
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Journal:
Authors:
Rheumatology, Osteoarthritis
1. Jul 2012
The inhibitory effect of salmon calcitonin on tri-iodothyronine induction of early hypertrophy in articular cartilage
OBJECTIVE:
Salmon calcitonin has chondroprotective effect both in vitro and in vivo, and is therefore being tested as a candidate drug for cartilage degenerative diseases. Recent studies have indicated that different chondrocyte phenotypes may express the calcitonin receptor (CTR) differentially. W…
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Journal:
Authors:
- Chen-An P,
- Andreassen KV,
- Henriksen K,
- Karsdal MA,
- Bay-Jensen AC,
Rheumatology, Osteoarthritis
15. Feb 2012
Mice over-expressing salmon calcitonin have strongly attenuated osteoarthritic histopathological changes after destabilization of the medial meniscus
OBJECTIVE:
Calcitonin is well-known for its inhibitory actions on bone-resorbing osteoclasts and recently potential beneficial effects on cartilage were shown. We investigated effects of salmon calcitonin (sCT) on the articular cartilage and bone, after destabilization of the medial meniscus (DMM) …
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Journal:
Authors:
- Sondergaard BC,
- Catala-Lehnen P,
- Huebner AK,
- Bay-Jensen AC,
- Schinke T,
- Henriksen K,
- Schilling S,
- Haberland M,
- Nielsen RH,
- Amling M,
- Karsdal MA,
Rheumatology, Osteoarthritis
18. Jan 2012
The distribution pattern of critically short telomeres in human osteoarthritic knees
INTRODUCTION
Telomere shortening is associated with a number of common age-related diseases. A role of telomere shortening in osteoarthritis (OA) has been suggested, mainly based on the assessment of mean telomere length in ex vivo expanded chondrocytes. We addressed this role directly in vivo by u…
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Journal:
Authors:
- Harbo M,
- Bendix L,
- Bay-Jensen AC,
- Graakjaer J,
- Søe K,
- Andersen TL,
- Kjaersgaard-Andersen P,
- Koelvraa S,
- Delaisse JM,
Rheumatology, Osteoarthritis, Rheumatoid Arthritis
8. Dec 2011
Molecular serum and urine marker repertoire supporting clinical research on joint diseases
The need for improved analytical techniques in the study of slow, degenerative diseases such as rheumatoid arthritis and osteoarthritis has driven major efforts aimed at identifying biochemical markers of pathological processes in both diseases. A series of novel biochemical markers has surfaced and…
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Journal:
Authors:
- Qvist P,
- Bay-Jensen AC,
- Christiansen C,
- Sondergaard BC,
- Karsdal MA,
Rheumatology, Osteoarthritis
13. Oct 2011
Identification of the calcitonin receptor in osteoarthritic chondrocytes
BACKGROUND:
Preclinical and clinical studies have shown that salmon calcitonin has cartilage protective effects in joint degenerative diseases, such as osteoarthritis (OA). However, the presence of the calcitonin receptor (CTR) in articular cartilage chondrocytes is yet to be identified. In this st…
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Journal:
Authors:
- Segovia-Silvestre T,
- Bonnefond C,
- Sondergaard BC,
- Christensen T,
- Karsdal MA,
- Bay-Jensen AC,
Rheumatology, Osteoarthritis
14. Jul 2011
Characterization of an Ex vivo Femoral Head Model Assessed by Markers of Bone and Cartilage Turnover
OBJECTIVE:
The pathophysiology of osteoarthritis involves the whole joint and is characterized by cartilage degradation and altered subchondral bone turnover. At present, there is a need for biological models that allow investigation of the interactions between the key cellular players in bone/cart…
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Journal:
Authors:
- Madsen SH,
- Goettrup AS,
- Thomsen G,
- Christensen ST,
- Schultz N,
- Henriksen K,
- Bay-Jensen AC,
- Karsdal MA,
Rheumatology, Osteoarthritis
19. Apr 2011
Oral salmon calcitonin reduces cartilage and bone pathology in an osteoarthritis rat model with increased subchondral bone turnover
OBJECTIVES:
Traumatic osteoarthritis (OA) is possibly augmented by effects from loss of sex hormones. Salmon calcitonin is shown to reduce OA pathogenesis and bone resorption. We investigated the effects of oral salmon calcitonin treatment and ovariectomy on cartilage and bone pathology in a trauma…
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Journal:
Authors:
- Nielsen RH,
- Bay-Jensen AC,
- Byrjalsen I,
- Karsdal MA,
Rheumatology, Osteoarthritis
13. Apr 2011
Enzyme-linked immunosorbent assay (ELISAs) for metalloproteinase derived type II collagen neoepitope, CIIM--increased serum CIIM in subjects with severe radiographic osteoarthritis
OBJECTIVES:
In joint degenerative diseases, the collagens are degraded by matrix metalloproteinases and protein fragments are released to serum as potential biomarkers.
METHODS:
A collagen type II specific neoepitope, CIIM, was identified (…RDGAAG(1053)) by mass spectrometry. Two ELISAs against…
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Journal:
Authors:
- Bay-Jensen AC,
- Liu Q,
- Byrjalsen I,
- Li Y,
- Wang J,
- Pedersen C,
- Leeming DJ,
- Dam EB,
- Zheng Q,
- Qvist P,
- Karsdal MA,
Rheumatology, Osteoarthritis
15. Mar 2011
A microarray analysis of full depth knee cartilage of ovariectomized rats
BACKGROUND:
This short communication focuses the on articular cartilage and the subchondral bone, both of which play important roles in the development of osteoarthritis (OA). There are indications that estrogen-deficiency, as the post-menopausal state, accelerate the development of OA.
FINDINGS…
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Journal:
Authors:
- Bay-Jensen AC,
- Nielsen RH,
- Segovia-Silvestre T,
- Azria M,
- Staedtler F,
- Letzkus M,
- Hartmann N,
- Brachat AH,
- Karsdal MA,
Rheumatology, Osteoarthritis
3. Jan 2011
Tummala SDiagnosis of Osteoarthritis by Cartilage Surface Smoothness Quantified Automatically from Knee MRI
OBJECTIVE:
We investigated whether surface smoothness of articular cartilage in the medial tibiofemoral compartment quantified from magnetic resonance imaging (MRI) could be appropriate as a diagnostic marker of osteoarthritis (OA).
METHOD:
At baseline, 159 community-based subjects aged 21 to 8…
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Journal:
Authors:
- Tummala S,
- Bay-Jensen AC,
- Karsdal MA,
- Dam EB,
Rheumatology, Osteoarthritis
17. Jun 2010
Biochemical markers identify influences on bone and cartilage degradation in osteoarthritis--the effect of sex, Kellgren-Lawrence (KL) score, body mass index (BMI), oral salmon calcitonin (sCT) treatment and diurnal variation
BACKGROUND:
Osteoarthritis (OA) involves changes in both bone and cartilage. These processes might be associated under some circumstances. This study investigated correlations between bone and cartilage degradation in patients with OA as a function of sex, Kellgren-Lawrence (KL) score, Body Mass In…
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Journal:
Authors:
Rheumatology, Osteoarthritis
15. May 2010
Aggrecanase- and matrix metalloproteinase-mediated aggrecan degradation is associated with different molecular characteristics of aggrecan and separated in time ex vivo
Aggrecan is one of the first proteins to be depleted from articular cartilage in early osteoarthritis. We investigated the molecular differences between matrix metalloproteinase (MMP)- and aggrecanase-mediated aggrecan degradation, as a consequence of their distinct time-dependent degradation profil…
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Journal:
Authors:
- Madsen SH,
- Sumer EU,
- Bay-Jensen AC,
- Sondergaard BC,
- Qvist P,
- Karsdal MA,
Rheumatology, Osteoarthritis
5. Apr 2010
Investigation of the direct effects of salmon calcitonin on human osteoarthritic chondrocytes
BACKGROUND:
Calcitonin has been demonstrated to have chondroprotective effects under pre-clinical settings. It is debated whether this effect is mediated through subchondral-bone, directly on cartilage or both in combination. We investigated possible direct effects of salmon calcitonin on proteogly…
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Journal:
Authors:
- Sondergaard BC,
- Madsen SH,
- Segovia-Silvestre T,
- Paulsen SJ,
- Christiansen T,
- Pedersen C,
- Bay-Jensen AC,
- Karsdal MA,
Rheumatology, Osteoarthritis
28. Feb 2010
Which elements are involved in reversible and irreversible cartilage degradation in osteoarthritis?
Osteoarthritis (OA) is a disease of the entire joint. Different treatment strategies for OA have been proposed and tested clinically without the desired efficacy. One reason for the scarcity of current chondroprotective agents may be the insufficient understanding of the patho-physiology of the join…
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Journal:
Authors:
- Bay-Jensen AC,
- Hoegh-Madsen S,
- Dam E,
- Henriksen K,
- Sondergaard BC,
- Pastoureau P,
- Qvist P,
- Karsdal MA,
Rheumatology, Osteoarthritis
15. Feb 2010
Application of biochemical markers in development of drugs for treatment of osteoarthritis
Osteoarthritis is a chronic disease for which no efficacious medical intervention is yet available. Recent disappointments in late-stage clinical development of disease-modifying osteoarthritic drugs (DMOADs) have precipitated efforts in biomarker discovery aimed at developing an analytical tool box…
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Journal:
Authors:
- Qvist P,
- Christiansen C,
- Karsdal MA,
- Madsen SH,
- Sondergaard BC,
- Bay-Jensen AC,
Rheumatology, Osteoarthritis
15. Jun 2009
Cartilage formation measured by a novel PIINP assay suggests that IGF-I does not stimulate but maintains cartilage formation ex vivo
OBJECTIVES:
The aim of this study was to investigate the time-dependent effect of insulin-like growth factor-I (IGF)-I on cartilage, evaluated by a novel procollagen type II N-terminal propeptide (PIINP) formation assay. This was performed in a cartilage model.
METHODS:
Bovine articular cartila…
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Journal:
Authors:
- Madsen SH,
- Sondergaard BC,
- Bay-Jensen AC,
- Karsdal MA,