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McGee-Lawrence M.,Georgia Regents University | Buckendahl P.,Rutgers University | Carpenter C.,Yale University | Henriksen K.,Nordic Bioscience Biomarkers and Research | And 2 more authors.
Journal of Experimental Biology | Year: 2015

Decreased physical activity in mammals increases bone turnover and uncouples bone formation from bone resorption, leading to hypercalcemia, hypercalcuria, bone loss and increased fracture risk. Black bears, however, are physically inactive for up to 6 months annually during hibernation without losing cortical or trabecular bone mass. Bears have been shown to preserve trabecular bone volume and architectural parameters and cortical bone strength, porosity and geometrical properties during hibernation. The mechanisms that prevent disuse osteoporosis in bears are unclear as previous studies using histological and serum markers of bone remodeling show conflicting results. However, previous studies used serum markers of bone remodeling that are known to accumulate with decreased renal function, which bears have during hibernation. Therefore, we measured serum bone remodeling markers (BSALP and TRACP) that do not accumulate with decreased renal function, in addition to the concentrations of serum calcium and hormones involved in regulating bone remodeling in hibernating and active bears. Bone resorption and formation markers were decreased during hibernation compared with when bears were physically active, and these findings were supported by histomorphometric analyses of bone biopsies. The serum concentration of cocaine and amphetamine regulated transcript (CART), a hormone known to reduce bone resorption, was 15-fold higher during hibernation. Serum calcium concentration was unchanged between hibernation and non-hibernation seasons. Suppressed and balanced bone resorption and formation in hibernating bears contributes to energy conservation, eucalcemia and the preservation of bone mass and strength, allowing bears to survive prolonged periods of extreme environmental conditions, nutritional deprivation and anuria. © 2015, Company of Biologists Ltd. All rights reserved.


Sun S.,Nordic Bioscience Biomarkers and Research | Bay-Jensen A.-C.,Nordic Bioscience Biomarkers and Research | Karsdal M.A.,Nordic Bioscience Biomarkers and Research | Siebuhr A.S.,Nordic Bioscience Biomarkers and Research | And 5 more authors.
BMC Musculoskeletal Disorders | Year: 2014

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 treatment. Hence, we aimed to develop a sensitive assay specifically measuring the active form of MMP-3 (act-MMP-3) both in ex vivo models and in human sera. Methods. A monoclonal antibody against the first 6 amino acids of act-MMP-3 was developed, and the specificity was carefully tested by comparing total and active MMP-3. A technically robust act-MMP-3 ELISA was produced. For biological validation, human synovial membrane and human cartilage explant (HEX) culture models were measured and compared by ELISA and immunoblots. For clinical relevance, the serum levels of act-MMP-3 in AS and RA patients before and after anti-TNF- treatment were evaluated. Results: A highly specific and technically robust ELISA detecting act-MMP-3 in serum was developed. The lower limit of detection was 33.7 pg/mL. The dilution and spiking recovery of human serum was within 100 ± 20%. The average intra- and inter-assay variations were 3.1% and 13.5% respectively.High levels of act-MMP-3 expression were observed in human synovial membrane culture and oncostatin M and TNF- stimulated human cartilage. In a cross-sectional study of both AS and RA patients, serum act-MMP-3 level was correlated with C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). In addition, in patients receiving anti-TNF- treatment, the serum level of act-MMP-3 was significantly reduced compared to baseline level reflecting the anti-inflammatory effects of the treatment. Conclusion: We have successfully developed an assay measuring act-MMP-3 in human serum showing correlation to inflammatory markers. Further studies are required to clarify, whether act-MMP-3 can serve as a predictive marker for outcome in chronic rheumatoid disorders. © 2014 Sun et al.; licensee BioMed Central Ltd.


PubMed | University of Southern Denmark, Vejle Hospital, Esbjerg Hospital and Nordic Bioscience Biomarkers and Research
Type: Journal Article | Journal: Arthritis research & therapy | Year: 2016

Psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA) are chronic inflammatory rheumatic diseases with complex origins. Both are characterized by altered extracellular matrix remodeling in joints and entheses that results in destructive and osteochondral proliferative lesions. There is a need for biomarkers reflecting core disease pathways for diagnosis and disease mapping. Pro-C2 reflects mature cartilage collagen type IIB formation, while C-Col10 represents turnover of type X collagen, which is exclusively expressed by hypertrophic chondrocytes. The objectives of this study were to study cartilage metabolism in axSpA and PsA by assessing Pro-C2 and C-Col10 and to evaluate their diagnostic utility against a healthy reference population.Patients with PsA (n=101) or axSpA (n=110) were recruited consecutively from three rheumatology outpatient clinics. Demographic and clinical disease measures were recorded. Pro-C2 and C-Col10 were quantified in serum by using newly developed and specific competitive enzyme-linked immunosorbent assays based on monoclonal antibodies. One-way analysis of variance and Tukeys multiple comparison tests were performed on log-transformed data. ROC curve analysis was carried out to evaluate their discriminative power.Pro-C2 levels in serum were significantly increased in both axSpA (median concentration 1.11ng/ml, 0.67-1.64) and PsA (median concentration 1.03ng/ml, 0.53-1.47) compared with healthy controls (median concentration 0.30ng/ml, 0.16-0.41) (p<0.0001). Pro-C2 did not differ according to treatment. C-Col10 was slightly but equally elevated in the PsA and axSpA groups vs. the control group, but it was significantly lower in patients with axSpA undergoing tumor necrosis factor- inhibitor (TNFi) treatment. ROC curve analysis revealed AUCs of 0.85 (95% CI 0.79-0.89) for axSpA and 0.81 (95% CI 0.75-0.86) for PsA.These findings indicate that cartilage collagen metabolism was enhanced in the axSpA and PsA groups compared with the healthy control group. The lower C-Col10 level in patients with axSpA undergoing TNFi treatment may reflect that hypertrophic chondrocytes in axSpA are targeted by TNFi. ROC curve analysis showed a diagnostic potential for Pro-C2 in axSpA and PsA.


Henriksen K.,Nordic Bioscience Biomarkers and Research | Byrjalsen I.,Nordic Bioscience Biomarkers and Research | Christiansen C.,Nordic Bioscience Biomarkers and Research | Karsdal M.A.,Nordic Bioscience Biomarkers and Research
Journal of Alzheimer's Disease | Year: 2014

Enzyme-generated fragments of tau have been linked to neuronal death and may serve as serum biomarkers of cognitive loss. Two competitive ELISAs detecting an ADAM10-generated fragment (Tau-A) or a caspase-3-generated fragment (Tau-C) were measured in baseline serum samples from patients with mild to moderate Alzheimer's disease (AD) from a Phase III clinical trial, and correlated to change in the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog11) and Clinical Dementia Rating-Sum of Boxes (CDR-SB) over a 64-week period using an MMRM-analysis. Relationship between the biomarkers and changes in ADAS-Cog11 score as a function of time were observed for Tau-C and change in ADAS-Cog11 (p = 0.06), and for Tau-A and change in CDR-SB (p = 0.04). The correlation of Tau-A/Tau-C ratio with cognitive change assessed by ADAS-Cog11 was even more significant (p < 0.006). These data indicate that measuring the balance between tau fragments in serum may provide a marker of the rate of progression of AD and warrant studies in larger cohorts. © 2015 - IOS Press and the authors.


Henriksen K.,Nordic Bioscience Biomarkers and Research | Christiansen C.,Nordic Bioscience Biomarkers and Research | Karsdal M.A.,Nordic Bioscience Biomarkers and Research
Climacteric | Year: 2015

Estrogen and bone health form a cornerstone of osteoporosis management. Diagnosis of osteoporosis is performed using bone mineral density (BMD), despite the limitations associated with this. Within the last 25 years, numerous bone turnover markers (BTM) have been developed, and this has led to a marked improvement in drug development for osteoporosis and understanding of fast bone losers. Estrogen research has provided landmark research on understanding the relationship between osteoporosis and BTMs. Clinical studies have illustrated how measurement of BTMs can assist in prediction of rapid bone loss, future fractures and, most importantly, the fracture efficacy of drugs. The BTMs provide information independent of BMD and fracture history. In addition, changes in bone turnover within 1 month predict later changes in BMD, which allows for early efficacy and prognostic measures. The aim is to provide a careful review of the possibilities that implementation of BTMs into clinical practice have provided, while placed in a historical context. The primary focus is on how the BTMs have revolutionized clinical trials on osteoporosis drugs through their ability to supplement bone mass measurements and fracture efficacy endpoints. © 2015 International Menopause Society.


Nedergaard A.,Nordic Bioscience Biomarkers and Research | Nedergaard A.,Bispebjerg Hospital building 8 Bispebjerg bakke 23 | Sun S.,Nordic Bioscience Biomarkers and Research | Karsdal M.A.,Nordic Bioscience Biomarkers and Research | And 6 more authors.
Journal of Cachexia, Sarcopenia and Muscle | Year: 2013

Background: Immobilization-induced loss of muscle mass is a complex phenomenon with several parallels to sarcopenic and cachectic muscle loss. Muscle is a large organ with a protein turnover that is orders of magnitude larger than most other tissues. Thus, we hypothesize that muscle loss and regain is reflected by peptide biomarkers derived from type VI collagen processing released in the circulation. Methods: In order to test this hypothesis, we set out to develop an ELISA assay against an type VI collagen N-terminal globular domain epitope (IC6) and measured the levels of IC6 and an MMP-generated degradation fragment of collagen 6, (C6M) in a human immobilization-remobilization study setup with young (n = 11) and old (n = 9) men. They were subjected to 2 weeks of unilateral lower limb immobilization followed by 4 weeks of remobilization including thrice weekly resistance training, using the contralateral leg as internal controls. Subjects were sampled for strength, quadriceps muscle volume and blood at baseline (PRE), post-immobilization (2W), and post-remobilization (4W). Blood were subsequently analyzed for levels of the C6M and IC6 biomarkers. We subsequently tested if there was any correlation between C6M, IC6, or the C6M/IC6 ratio and muscle mass or strength at baseline. We also tested whether there was any relation between these biomarkers and changes in muscle mass or strength with immobilization or remobilization. Results: The model produced significant loss of muscle mass and strength in the immobilized leg. This loss was bigger in young subjects than in elderly, but whereas the young recovered almost fully, the elderly had limited regrowth of muscle. We found a significant correlation between IC6 and muscle mass at baseline in young subjects (R 2 = 0.6563, p = 0.0045), but none in the elderly. We also found a significant correlation between C6M measured at the 4W time point and the change in muscle mass during remobilization, again only manifesting in the young men(R 2 = 0.6523, p = 0.0085). This discrepancy between the young and the elderly may be caused in part by much smaller changes in muscle mass in the elderly and partly by the relative small sample size. Conclusion: While we cannot rule out the possibility that these biomarkers in part stem from other tissues, our results strongly indicate that these markers represent novel biomarkers of muscle mass or change in muscle mass in young men. © 2013 Springer-Verlag Berlin Heidelberg.


Henriksen K.,Nordic Bioscience Biomarkers and Research | Thudium C.S.,Nordic Bioscience Biomarkers and Research | Christiansen C.,Nordic Bioscience Biomarkers and Research | Karsdal M.A.,Nordic Bioscience Biomarkers and Research
Expert Opinion on Therapeutic Targets | Year: 2015

Introduction: Osteoporosis is a major health care problem, and whereas efficacious treatments for vertebral fracture reduction are available for osteoporosis patients, these therapies are still limited with respect to capacity for restoration of bone loss, as well as efficacy on non-vertebral fractures, such as hip fractures, which are the source of morbidity and mortality.Areas covered: Studies of rare bone diseases in humans, such as osteopetrosis, sclerosteosis, pycnodysostosis and more, have shed light on a series of drug targets in bone that have the potential to result in therapies for osteoporosis with novel mechanisms of action, and the potential to improve the standard of care substantially. We focus on how they are separated from classic treatments for osteoporosis, in terms of novel modes of action, additional beneficial effects on bone turnover and importantly also safety. We focus on the status of anti-sclerostin antibodies, novel parathyroid hormone-related protein analogs, inhibitors of cathepsin K and ClC-7 in osteoclasts, all of which are currently in development.Expert opinion: There is a good possibility that the treatment of osteoporosis will be greatly improved within the coming years; however, with numerous effective and safe drugs already available careful attention to the safety of these novel candidates is crucial. © 2015 © 2015 Taylor & Francis.


Nedergaard A.,Nordic Bioscience Biomarkers and Research | Nedergaard A.,Bispebjerg Hospital | Henriksen K.,Nordic Bioscience Biomarkers and Research | Karsdal M.A.,Nordic Bioscience Biomarkers and Research | Christiansen C.,Nordic Bioscience Biomarkers and Research
Best Practice and Research: Clinical Obstetrics and Gynaecology | Year: 2013

Loss of musculoskeletal mass and function is a natural ageing trait, reinforced by an unhealthy life style. Loss of bone (osteoporosis) and muscle (sarcopaenia) are conditions whose prevalence are increasing because of the change in population distribution in the western world towards an older mean age. Improvements in lifestyle factors, such as diet, smoking and exercise, are the most powerful tools to combat this decline efficiently; however, public health interventions aimed at tackling these problems have shown abysmal success at the population level, mostly due to failure in compliance. With these issues in mind, we believe that the primary prevention modality in coming decades will be pharmacological. We review the basic biology of musculoskeletal ageing and what measures can be taken to prevent ageing-associated loss of musculoskeletal mass and function, with particular emphasis on pharmacological means. © 2013 Elsevier Ltd. All rights reserved.


Henriksen K.,Nordic Bioscience Biomarkers and Research | Karsdal M.A.,Nordic Bioscience Biomarkers and Research | John Martin T.,St. Vincent's Institute
Calcified Tissue International | Year: 2014

In the bone remodeling process that takes place throughout the skeleton at bone multicellular units, intercellular communication processes are crucial. The osteoblast lineage has long been known to program osteoclast formation and hence resorption, but the preservation of bone mass and integrity requires tight control of remodeling. This needs local controls that ensure availability of mesenchymal precursors and the provision of local signals that promote differentiation through the osteoblast lineage. Some signals can come from growth factors released from resorbed bone matrix, and there is increasing evidence that the osteoclast lineage itself produces factors that can either enhance or inhibit osteoblast differentiation and hence bone formation. A number of such factors have been identified from predominantly in vitro experiments. The coupling of bone formation to resorption is increasingly recognized as a complex, dynamic process that results from the input of many local factors of cell and matrix origin that can either promote or inhibit bone formation. © 2013 Her Majesty the Queen in Right of Australia.


PubMed | Medical University of Bialystok, Brown University, Pfizer, Mayo Medical School and 13 more.
Type: Journal Article | Journal: Alzheimer's & dementia : the journal of the Alzheimer's Association | Year: 2016

The last decade has seen a substantial increase in research focused on the identification of blood-based biomarkers that have utility in Alzheimers disease (AD). Blood-based biomarkers have significant advantages of being time- and cost-efficient as well as reduced invasiveness and increased patient acceptance. Despite these advantages and increased research efforts, the field has been hampered by lack of reproducibility and an unclear path for moving basic discovery toward clinical utilization. Here we reviewed the recent literature on blood-based biomarkers in AD to provide a current state of the art. In addition, a collaborative model is proposed that leverages academic and industry strengths to facilitate the field in moving past discovery only work and toward clinical use. Key resources are provided. This new public-private partnership model is intended to circumvent the traditional handoff model and provide a clear and useful paradigm for the advancement of biomarker science in AD and other neurodegenerative diseases.

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