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Background: Activin A has been shown to enhance osteoclast activity and its inhibition results in bone growth. The potential role of activin A as a marker of chronic kidney disease-mineral bone disease (CKD-MBD) and its relationship with other markers has not been studied in children with CKD., Methods: A cross sectional study was conducted among 40 children aged 2 to 18 years with CKD (Stage 2 to 5; 10 in each stage) and 40 matched controls. Activin A, cathepsin K, FGF-23, PTH, serum calcium, phosphorous and alkaline phosphatase in both groups were measured and compared. The correlation of activin A and markers of CKD-MBD was studied. A p value of < 0.05 was considered significant., Results: The mean age of children with CKD was 9.30 ± 3.64 years. Mean levels of activin A in cases were 485.55 pg/ml compared to 76.19 pg/ml in controls (p < 0.001). FGF-23 levels in cases were 133.18 pg/ml while in controls it was 6.93 pg/ml (p < 0.001). Mean levels of cathepsin K were also significantly higher in cases as compared to controls. There was a progressive increase in activin A and cathepsin K levels with increasing stage of CKD. Activin A had a significant positive correlation with serum creatinine (r = 0.51; p < 0.001)., Conclusions: Activin A levels progressively rise with advancing CKD stage. These findings suggest that activin A can be a potential early marker of CKD-MBD in children., (© 2024. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Background: Osteoclast cell increase is a major risk factor for osteoporosis and degenerative bone and joint diseases. At present, RANKL and M-CSF are commonly used to induce osteoclastogenesis. Thioacetamide (TAA) can lead to many types of liver and kidney damage, but less attention has been paid to the association of TAA with bone damage. In this work, we investigated the effects of TAA on the osteoclastogenesis and differentiation of bone marrow macrophages (BMMs)., Methods: BMMs of SD rat suckling mice were taken for primary culture. CCK-8 was used to detect the toxic effects of TAA on BMMs, and flow cytometry was used to detect the effects of TAA on the cell cycle, cell viability, apoptosis and intracytoplasmic Ca 2+ concentration of BMMs. TRAP staining was used to detect the effect of RANKL and M-CSF and TAA on osteoclast differentiation of BMMs. Western Blot was used to detect the expression level of PI3K/AKT pathway and osteoclast-specific proteins (TRAP and cathepsin K)., Results: The results suggested that TAA inhibited the proliferation of BMMs, while enhancing osteoclastogenesis at 0.5 mg/mL and 1 mg/mL as assayed by TRAP staining. Exposed to TAA, BMMs could differentiate into osteoclast-like cells with overexpression of cathepsin K and TRAP proteins. Western blot results showed that TAA can activate the expression levels of P-PI3K, P-AKT, P-P38, and P-JNK, accompanied by apoptosis of BMMs and increase in intracellular Ca 2+ ., Conclusion: TAA may induce osteoclast formation in BMMs by activating the expression of PI3K/AKT pathway proteins, which is comparable to the classic osteoclast differentiation inducer RANKL and M-CSF. This suggests that we may find a cheap osteoclast inducer., (© 2022. The Author(s).)

Purpose: Cardiovascular (CV) disease remains the leading cause of mortality among end-stage kidney disease (ESKD) patients. Cathepsin-K (CatK), a small cysteine protease involved in bone and extracellular matrix remodeling, has recently emerged as a key-factor in the pathogenesis of various conditions predisposing to CV disease, including atherosclerosis, obesity, diabetes, and vascular calcification. In this pilot prospective study, we aimed at evaluating the clinical significance and the predictive power of CatK in a small cohort of hemodialysis (HD) patients., Methods: Cathepsin-K was measured in 54 prevalent HD patients and in 30 controls together with routine parameters. Patients were then followed up to 26 months and the time of cardiovascular death (endpoint of the study prospective phase) recorded., Results: CatK levels were increased in the HD cohort as compared with controls (p < 0.001). In HD patients, CatK was also independently correlated to PTH (β = 0.368; p = 0.001), alkaline phosphatase (β = 0.383; p < 0.001), C-reactive protein (β = 0.260; p = 0.01), and white cell count (β = - 0.219; p = 0.02). After baseline assessment, patients were followed for CV death (mean follow-up 24.8 ± 3.1 months). Kaplan-Meier analysis showed a worsen survival (log-rank p = 0.04) in HD patients with CatK levels > 440 pg/mL (best ROC-derived cut-off with 69.6% sensitivity and 79.8% specificity) with a crude HR (Mantel-Haenszel) of CV death of 3.46 (95% CI 1.89-13.44)., Conclusions: In prevalent HD patients, altered CatK levels may reflect mineral dysmetabolism and inflammation, and predict CV death in the mid-term. These preliminary findings prompt the rationale for further investigations on larger cohorts to validate CatK as a biomarker for improving CV risk stratification in ESKD.

Ovariohysterectomized (OHE) female dogs do not develop the osteopenia and osteoporosis associated with decreasing estrogen in post-menopausal women, possibly due to post-OHE bone mineral density retention through a mechanism that remains unclear. In this study, we aimed to elucidate this mechanism by investigating estradiol (E2) and bone markers. Samples were collected from 56 OHE and 43 intact bitches (0.33 to 17.58 years old) and analyzed for serum E2, osteoclast-secreted cysteine protease cathepsin K (CTK), and N-telopeptide of type I collagen (NTx) by ELISA. OHE and intact bitches showed no significant difference in serum E2 or NTx, and there was no correlation between serum E2 and NTx and age and time since OHE. Intact bitches showed a very low correlation between E2 and NTx, but OHE bitches showed no correlation, and serum CTK was generally undetectable in both groups. Our findings suggest the influence of gonadal hormones on bone metabolism does not work effectively in dogs; this is consistent with a shorter duration of exposure to E2 in bitches (through the 4-to-8-month anestrus phase) than women., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Cathepsin K plays an important role in bone resorption. The reports of the association of serum cathepsin K with bone mineral density (BMD) and bone turnover markers are conflicting and the role of serum cathepsin K as a bone turnover marker is unclear. The aims of the study were as follows: (1) to investigate the association of serum cathepsin K with BMD and markers of bone turnover and (2) to evaluate the correlations of single-nucleotide polymorphisms (SNPs) within the CTSK gene with serum cathepsin K, BMD, and markers of bone metabolism in postmenopausal Chinese women. A cross-sectional study was conducted with 1752 postmenopausal Chinese women. Four tagging SNPs (rs12085336, rs12746973, rs4379678, and rs10847) of the CTSK gene were genotyped. Serum cathepsin K of 768 and markers of bone metabolism of 1752 including serum intact PTH, 25-hydroxyvitamin D [25(OH)D], procollagen type 1 N-terminal propeptide (P1NP), and β-CrossLaps of type I collagen containing cross- linked C-telopeptide (β-CTX) were measured. The BMD of the lumbar spine and proximal femur were measured by dual-energy X-ray absorptiometry (DXA). No significant relationship was detected between serum cathepsin K and age, BMI, BMD or bone metabolic markers (all P > 0.05) after adjustment for age and BMI. We failed to identify any significant association between the genotypes or haplotypes of CTSK and BMD, bone turnover markers, or serum cathepsin K. Neither serum cathepsin K nor CTSK gene polymorphisms was correlated with BMD or bone turnover markers. Genetic polymorphisms of CTSK may not be a major contributor to variations in the serum cathepsin K or BMD in postmenopausal Chinese women. The results implied that serum cathepsin K may not be viewed as a substitute for bone turnover markers., (Copyright © 2020 Gao, Li, Yue and Zhang.)

Background: Extracellular matrix metabolism and cardiac cell death participate centrally in myocardial infarction (MI). This study tested the roles of collagenolytic cathepsin K (CatK) in post-MI left ventricular remodeling., Methods and Results: Patients with acute MI had higher plasma CatK levels (20.49 ± 7.07 pmol/L, n = 26) than those in subjects with stable angina pectoris (8.34 ± 1.66 pmol/L, n = 28, P = .01) or those without coronary heart disease (6.63 ± 0.84 pmol/L, n = 93, P = .01). CatK protein expression increases in mouse hearts at 7 and 28 days post-MI. Immunofluorescent staining localized CatK expression in cardiomyocytes, endothelial cells, fibroblasts, macrophages, and CD4 + T cells in infarcted mouse hearts at 7 days post-MI. To probe the direct participation of CatK in MI, we produced experimental MI in CatK-deficient mice (Ctsk -/- ) and their wild-type (Ctsk +/+ ) littermates. CatK-deficiency yielded worsened cardiac function at 7 and 28 days post-MI, compared to Ctsk +/+ littermates (fractional shortening percentage: 5.01 ± 0.68 vs. 8.62 ± 1.04, P < .01, 7 days post-MI; 4.32 ± 0.52 vs. 7.60 ± 0.82, P < .01, 28 days post-MI). At 7 days post-MI, hearts from Ctsk -/- mice contained less CatK-specific type-I collagen fragments (10.37 ± 1.91 vs. 4.60 ± 0.49 ng/mg tissue extract, P = .003) and more fibrosis (1.67 ± 0.93 vs. 0.69 ± 0.20 type-III collagen positive area percentage, P = .01; 14.25 ± 4.12 vs. 6.59 ± 0.79 α-smooth muscle actin-positive area percentage, P = .016; and 0.82 ± 0.06 vs. 0.31 ± 0.08 CD90-positive area percentage, P = .008) than those of Ctsk +/+ mice. Immunostaining demonstrated that CatK-deficiency yielded elevated cardiac cell death but reduced cardiac cell proliferation. In vitro studies supported a role of CatK in cardiomyocyte survival., Conclusion: Plasma CatK levels are increased in MI patients. Heart CatK expression is also elevated post-MI, but CatK-deficiency impairs post-MI cardiac function in mice by increasing myocardial fibrosis and cardiomyocyte death., (Copyright © 2018. Published by Elsevier Ltd.)

Background: Axial spondyloarthritis (axSpA) is characterized by significant bone loss caused by dysregulation of physiological bone turnover, possibly resulting from intensified differentiation of osteoclasts. The aim of this study was to reevaluate the levels of osteoclastogenesis-mediating factors: soluble RANKL, M-CSF, OPG and other cytokines in sera of untreated, with sDMARDs and/or bDMARDs, axSpA patients and to test whether these sera influence differentiation of healthy monocytes towards osteoclast lineage., Methods: Bone remodeling molecules (RANKL, M-CSF, OPG, IL-6, OSM, IL-17A, TGFβ, and TNFα) were evaluated in 27 patients with axSpA and 23 age and sex-matched controls. Disease activity (BASDAI, ASDAS) and inflammatory markers (ESR, CRP) were assessed. Monocytes obtained from healthy individuals were cultured in vitro in presence of sera from 11 randomly chosen axSpA patients and 10 controls, with addition of exogenous M-CSF and/or RANKL or without. Osteoclastic differentiation was assessed analyzing osteoclast markers (cathepsin K and RANK at mRNA level) and with osteoclast-specific staining., Results: axSpA patients' sera levels of soluble RANKL were significantly lower and M-CSF, IL-6, OSM, IL-17A and TNFα significantly higher in comparison to controls, whereas of OPG and TGFβ were comparable in both groups. Numbers of generated in vitro osteoclasts and cathepsin K mRNA levels did not differ between cultures supplemented with sera of healthy and axSpA patients, both in the absence and presence of M-CSF. Instead, addition of exogenous RANKL boosted osteoclastogenesis, which was significantly higher in cultures with axSpA sera. Furthermore, sera from axSpA patients induced substantially higher levels of RANK mRNA, independently of M-CSF and RANKL stimulation., Conclusion: We show that, paradoxically, serum levels of soluble RANKL observed in axSpA are in fact significantly lower in comparison to healthy blood donors. Our results indicate that sera of axSpA patients - in contrary to healthy subjects - contain circulating, soluble factors (presumably IL-6, OSM, IL-17A, TNFα and others) able to stimulate healthy monocytes responsiveness to even relative low RANKL serum levels, by inducing high RANK mRNA expression and - as a net effect - boosting their osteoclastogenic potential. We suggest also that locally produced RANKL in axSpA may induce overactive osteoclasts from their precursors.

Periostin is a matricellular protein involved in bone formation and bone matrix organization, but it is also produced by other tissues. Its circulating levels have been weakly associated with bone microstructure and prevalent fractures, possibly because periostin measured by the current commercial assays does not specifically reflect bone metabolism. In this context, we developed a new ELISA for a periostin fragment resulting from cathepsin K digestion (K-Postn). We hypothesized that circulating K-Postn levels could be associated with bone fragility. A total of 695 women (age 65.0 ± 1.5 years), enrolled in the Geneva Retirees Cohort (GERICO), were prospectively evaluated over 4.7 ± 1.9 years for the occurrence of low-trauma fractures. At baseline, we measured serum periostin, K-Postn, and bone turnover markers (BTMs), distal radius and tibia microstructure by HR-pQCT, hip and lumbar spine aBMD by DXA, and estimated fracture probability using the Fracture Risk Assessment Tool (FRAX). Sixty-six women sustained a low-trauma clinical fracture during the follow-up. Total periostin was not associated with fractures (HR [95% CI] per SD: 1.19 [0.89 to 1.59], p = 0.24). In contrast, K-Postn was significantly higher in the fracture versus nonfracture group (57.5 ± 36.6 ng/mL versus 42.5 ± 23.4 ng/mL, p < 0.001) and associated with fracture risk (HR [95%CI] per SD: 2.14 [1.54 to 2.97], p < 0.001). After adjustment for aBMD, FRAX, bone microstructure, or BTMs, K-Postn remained significantly associated with fracture risk. The performance of the fracture prediction models was improved by adding K-Postn to aBMD or FRAX (Harrell C index for fracture: 0.70 for aBMD + K-Post versus 0.58 for aBMD alone, p = 0.001; 0.73 for FRAX + K-Postn versus 0.65 for FRAX alone, p = 0.005). Circulating K-Postn predicts incident fractures independently of BMD, BTMs, and FRAX in postmenopausal women. Hence measurement of a periostin fragment resulting from in vivo cathepsin K digestion may help to identify subjects at high risk of fracture. © 2017 American Society for Bone and Mineral Research., (© 2017 American Society for Bone and Mineral Research.)

Despite extensive investigations, the process of development of chronic subdural hematoma (CSDH) is not known. The present study aims to investigate CSDH by measuring biomarkers in it, gas analysis, and immunohistochemical examination. A total of 42 patients with symptomatic CSDH who underwent burr-hole drainage were enrolled. Intraoperatively, hematoma fluid and peripheral venous blood (PV CSDH ) were simultaneously collected. As controls, peripheral venous blood (PV Control ) and intracranial cerebrospinal fluid (CSF) were collected from other subjects during other surgeries. CatK, lipocalin-type prostaglandin D synthase (PGDS), and cystatin C (CysC) present in these specimens were measured using enzyme-linked immunosorbent assay. Data obtained were statistically analyzed after age correction. In 15 patients, gas analysis was performed for CSDH and PV CSDH . Furthermore, immunohistochemical examination for the outer membrane was performed for four patients. CatK, PGDS, and CysC levels were markedly elevated in the CSF and CSDH. CatK levels in PV CSDH were significantly higher than in PV Control (P<0.0001). In contrast, CysC levels in PV CSDH were significantly lower than in PV Control (P=0.004). The gas analysis revealed that the internal environment of CSDH is characterized by marked hypoxia, hypoglycemia, and lactic acidosis. Furthermore, the outer membrane consistently showed a diffuse staining for CatK. Based on these, CatK was thought to play a role in the development of CSDH, with the levels in peripheral venous blood elevated in patients with CSDH., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Objectives: To investigate serum biomarkers, tartrate resistant acid phosphatase 5b (TRAcP5b) and cathepsin K (cath-K), indicative of osteoclastic bone resorption, and their relationship to pain and pain change in knee osteoarthritis (OA)., Methods: Sera and clinical data were collected from 129 people (97 with 3-year follow-up) with knee OA from the Prediction of Osteoarthritis Progression (POP) cohort. Knee OA-related outcomes in POP included: WOMAC pain, National Health and Nutrition Examination Survey (NHANES) I (pain, aching and stiffness), subchondral sclerosis, and radiographically determined tibiofemoral and patellofemoral OA. Two putative osteoclast biomarkers were measured in sera: TRAcP5b and cath-K. Medial tibia plateaux were donated at knee arthroplasty for symptomatic OA (n = 84) or from 16 post mortem (PM) controls from the Arthritis Research UK (ARUK) Pain Centre joint tissue repository. Osteoclasts were stained for tartrate resistant acid phosphatase (TRAcP) within the subchondral bone of the medial tibia plateaux., Results: Serum TRAcP5b activity, but not cath-K-immunoreactivity, was associated with density of TRAcP-positive osteoclasts in the subchondral bone of medial tibia plateaux. TRAcP-positive osteoclasts were more abundant in people with symptomatic OA compared to controls. Serum TRAcP5b activity was associated with baseline pain and pain change., Conclusions: Our observations support a role for subchondral osteoclast activity in the generation of OA pain. Serum TRAcP5b might be a clinically relevant biomarker of disease activity in OA., (Copyright © 2017 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

The correlation of in vitro inhibition of cathepsin K (CatK) activity and in vivo suppression of collagen I biomarkers was examined with three selective CatK inhibitors to explore the potential translatability from animal species to human. These inhibitors exhibited good in vitro potencies toward recombinant CatK enzymes across species, with IC 50 values ranging from 0.20 to 6.1 nM. In vivo studies were conducted in animal species following multiple-day dosing of the CatK inhibitors to achieve steady-state plasma drug concentration-time profiles. Measurement of urinary bone resorption biomarkers (cross-linked N-terminal telopeptide and helical peptide of type I collagen) revealed drug concentration-dependent suppression of biomarkers, with EC 50 values estimated to be 12 to 160 nM. Marked improvement in the correlation between in vitro and in vivo CatK activities was observed with the application of unbound (free) fraction in plasma, consistent with the conditions stipulated by the free-drug hypothesis. These results indicate that the in vitro-in vivo translation of CatK inhibition observed in animal species can translate to humans when the unbound fraction of the inhibitor is considered. Interestingly, residual levels of urinary bone resorption marker were detected as the suppression reached saturation (at an average of 82% inhibition), an apparent phenomenon observed regardless of the species, biomarker, or compound examined. Since cathepsin enzymes other than CatK were reported to catalyze cleavage of collagen I, it is hypothesized that CatK-mediated degradation of collagen I in bone represents ~82% of overall collagen I turnover in the body.

Cysteinyl cathepsin K (CatK) is expressed in osteoclasts to mediate bone resorption, but is also inducible under inflammatory conditions. Fas lpr mice on a C57BL/6 background develop spontaneous systemic lupus erythematosus-like manifestations. Although normal mouse kidneys expressed negligible CatK, those from Fas lpr mice showed elevated CatK expression in the glomeruli and tubulointerstitial space. Fas lpr mice also showed elevated serum CatK levels. CatK deficiency in Fas lpr mice reduced all tested kidney pathologies, including glomerulus and tubulointerstitial scores, glomerulus complement C3 and IgG deposition, chemokine expression and macrophage infiltration, and serum autoantibodies. CatK contributed to Fas lpr mouse autoimmunity and pathology in part by its activity in TLR-7 proteolytic processing and consequent regulatory T (Treg) cell biology. Elevated TLR7 expression and proteolytic processing in Fas lpr mouse kidneys and Tregs showed significantly reduced levels in CatK-deficient mice, leading to increased spleen and kidney Treg content. Purified CD4 + CD25 high Foxp3 + Tregs from CatK-deficient mice doubled their immunosuppressive activity against T effector cells, compared with those from CatK-sufficient mice. In Fas lpr mice, repopulation of purified Tregs from CatK-sufficient mice reduced spleen sizes, autoantibody titers, and glomerulus C3 and IgG deposition, and increased splenic and kidney Treg contents. Tregs from CatK-deficient mice had significantly more potency than CatK-sufficient Tregs in reducing spleen sizes, serum autoantibody titers, and glomerulus C3 deposition, and in increasing splenic and kidney Treg content. This study established a possible role of CatK in TLR7 proteolytic activation, Treg immunosuppressive activity, and lupus autoimmunity and pathology., (Copyright © 2017 by The American Association of Immunologists, Inc.)

Background: The aim of this study was to evaluate the plasma levels of bone turnover markers (BTMs) in male patients with stable angina depending on the bone mineral density (BMD), coronary atherosclerosis (CA) and coronary artery calcification (CAC)., Methods: We recruited 112 males with verified stable angina. All the patients underwent coronary angiography, multislice spiral computed tomography, and dual-energy X-ray absorptiometry. Plasma levels of BTMs were measured by enzyme-linked immunosorbent assay., Results: Osteopoenia and osteoporosis were reported in 90 (80.4%) and 34 (30.4%) patients, respectively. Multivessel coronary artery disease, severe CA and CAC, decreased cathepsin K plasma level, and increased osteocalcin plasma level were significantly more prevalent in patients with osteopoenia/osteoporosis compared to the subjects with normal BMD. Patients with severe CA and CAC had significantly reduced cathepsin K plasma levels., Conclusions: We revealed a significant association of osteopoenia/osteoporosis with severe CA and CAC in males with stable angina. Cathepsin K and osteocalcin plasma levels may be suggested as the significant markers of osteopoenia/osteoporosis. In addition, cathepsin K plasma level can be also a valuable marker of severe CA and CAC., (Copyright © 2016 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.)

Chronic kidney disease (CKD) is a cause of coronary artery calcification (CAC) and an independent predictor of major adverse cardiac and cerebrovascular events (MACCE). Cathepsin K (CatK) is a lysosomal cysteine protease which affects vascular calcification and glucose metabolism disorder. We investigated the relationships among CatK, CAC, diabetes mellitus (DM) and MACCE in CKD patients. 113 consecutive CKD patients were enrolled. Their CAC was evaluated by computed tomography. Their plasma CatK level was measured by ELISA. They were divided into two groups by CatK levels and followed up for up to 3 years. The impact of CatK was analyzed in all participants, diabetic patients and non-diabetic patients. Kaplan-Meier analysis demonstrated a significant higher incidence of MACCE in the high CatK group (P = 0.028). The CatK level was significantly higher in patients with MACCE compared to that in patients without MACCE (P = 0.034). Cox's model revealed the higher plasma CatK and BNP level as independent predictors of MACCE (P = 0.043 and P < 0.01, respectively). Only in non-diabetic patients, there was a significant correlation between CatK and CAC score, and high CatK group had a significant higher level of LDL-C and LDL-C/HDL-C ratio (P < 0.05 and P < 0.001, respectively) than low CatK group. And these lipid disorders were independent predictors of CatK elevation. In CKD patients, our results indicated an impact of higher CatK level on their MACCE. The significant association among the CatK level, CAC and MACCE was found in non-diabetic CKD patients.

Background and Objective: Gaucher disease is an inherited disorder caused by deficit of acid β-glucocerebrosidase, responsible for the degradation of glucosylceramide to ceramide and glucose. Although the disorder is primarily hematologic, bone is the second most commonly affected structure. Cathepsin K (CATK) is an enzyme involved in bone remodelling process. It has been proposed that determination of its serum concentrations may provide additional information to other biomarkers., Patients and Methods: The study included 20 control subjects and 20 Gaucher type 1 patients from Andalusia and Extremadura regions. We analyzed the biomarkers of bone remodelling: the bone alkaline phosphatase (B-ALP), the N-terminal propeptide of type 1 procollagen (P1NP), the β carboxyterminal telopeptide of type 1 collagen (CTx) and the CATK through electrochemiluminescence and immunoassay techniques., Results: There is an increase in levels of CATK, CATK/P1NP and CATK/B-ALP ratios in type 1 Gaucher patients compared to the control group. Considering the existence of skeletal manifestations in the patient group, the CATK and CATK/P1NP ratio showed higher levels in patients with bone damage compared to those without it., Conclusions: Although imaging studies are the gold standard for monitoring bone disease in type 1 Gaucher patients, the utility of CATK should be considered as a possible indicator of bone damage in these patients. Furthermore, this parameter can be used in the monitoring of the treatment of bone pathology., (Copyright © 2015 Elsevier España, S.L.U. All rights reserved.)

Cysteinyl cathepsin K (CatK) is one of the most potent mammalian collagenases involved in cardiovascular disease. Here, we investigated the clinical predictive value of serum CatK levels in patients with chronic heart failure (CHF). We examined 134 patients with CHF, measuring their serum CatK, troponin I, high-sensitive C-reactive protein, and pre-operative N-terminal pro-brain natriuretic peptide levels. The patients were divided into two groups: the 44 patients who showed a left ventricular (LV) ejection fraction (LVEF) < 40% (the "lowLVEF" group) and the 90 patients showing LVEF values ≥ 40% (the "highLVEF" group). The lowLVEF patients had significantly higher serum CatK levels compared to the highLVEF patients (58.4 ± 12.2 vs. 44.7 ± 16.4, P < 0.001). Overall, a linear regression analysis showed that CatK levels correlated negatively with LVEF (r = -0.4, P < 0.001) and positively with LV end-diastolic dimensions (r = 0.2, P < 0.01), LV end-systolic dimensions (r = 0.3, P < 0.001), and left atrial diameters (r = 0.3, P < 0.01). A multiple logistic regression analysis showed that CatK levels were independent predictors of CHF (odds ratio, 0.90; 95% confidence interval, 0.84-0.95; P < 0.01). These data indicate that elevated levels of CatK are closely associated with the presence of CHF and that the measurement of circulating CatK provides a noninvasive method of documenting and monitoring the extent of cardiac remodeling and dysfunction in patients with CHF.

Background: Regular physical activities have a positive effect on the muscular skeletal system but overstrenuous exercise may be different. Transiently suppressed bone formation and increased bone resorption after participation in a 246-km ultradistance race has been demonstrated., Purpose: The aim of this study was to analyze effects of the Spartathlon race on novel musculoskeletal markers., Methods: Venous blood samples were obtained before and immediately after the race from 19 participants of the Spartathlon. From 9 runners who were available 3 days after the start blood was drawn for a third time. Serum levels of myostatin, an inhibitor of myogenic differentiation, and its opponent follistatin as well as sclerostin and dickkopf-1, both of them inhibitors of the wnt signaling pathway, and markers of bone turnover were determined., Results: Serum levels of myostatin were significantly higher after the race. Serum follistatin only showed a transient increase. Sclerostin levels did not significantly differ before and after the race, whereas dickkopf-1 levels were significantly decreased. At follow-up a decrement of sclerostin and dickkopf-1 levels was seen. Serum cathepsin K levels did not change., Conclusion: The increase of serum levels of myostatin appears to reflect muscle catabolic processes induced by overstrenuous exercise. After the short-term uncoupling of bone turnover participation in an ultradistance race seems to initiate a long-term positive effect on bone indicated by the low-level inhibition of the Wnt/β-catenin signaling pathway.

Purpose: Cathepsin K is a potent collagenase implicated in human and animal atherosclerosis-based vascular remodeling. This study examined the hypothesis that serum CatK is associated with the prevalence of coronary artery disease (CAD)., Materials and Methods: Between January 2011 and December 2012, 256 consecutive subjects were enrolled from among patients who underwent coronary angiography and percutaneous coronary intervention treatment. A total of 129 age-matched subjects served as controls., Results: The subjects' serum cathepsin K and high sensitive C-reactive protein (hs-CRP) and high-density lipoprotein cholesterol were measured. The patients with CAD had significantly higher serum cathepsin K levels compared to the controls (130.8±25.5 ng/mL vs. 86.9±25.5 ng/mL, p<0.001), and the patients with acute coronary syndrome had significantly higher serum cathepsin K levels compared to those with stable angina pectoris (137.1±26.9 ng/mL vs. 102.6±12.9 ng/mL, p<0.001). A linear regression analysis showed that overall, the cathepsin K levels were inversely correlated with the high-density lipoprotein levels (r=-0.29, p<0.01) and positively with hs-CRP levels (r=0.32, p<0.01). Multiple logistic regression analyses shows that cathepsin K levels were independent predictors of CAD (odds ratio, 1.76; 95% confidence interval, 1.12 to 1.56; p<0.01)., Conclusion: These data indicated that elevated levels of cathepsin K are closely associated with the presence of CAD and that circulating cathepsin K serves a useful biomarker for CAD.

Major advances in highly active antiretroviral therapies (HAART) have extended the lives of people living with HIV, but there still remains an increased risk of death by cardiovascular diseases (CVD). HIV proteins have been shown to contribute to cardiovascular dysfunction with effects on the different cell types that comprise the arterial wall. In particular, HIV-1 transactivating factor (Tat) has been shown to bind to endothelial cells inducing a range of responses that contribute to vascular dysfunction. It is well established that hemodynamics also play an important role in endothelial cell mediated atherosclerotic development. When exposed to low or oscillatory shear stress, such as that found at branches and bifurcations, endothelial cells contribute to proteolytic vascular remodeling by upregulating cathepsins, potent elastases and collagenases that contribute to altered biomechanics and plaque formation. Mechanisms to understand the influence of Tat on shear stress mediated vascular remodeling have not been fully elucidated. Using an in vivo HIV-Tg mouse model and an in vitro cone and plate shear stress bioreactor to actuate physiologically relevant pro-atherogenic or atheroprotective shear stress on human aortic endothelial cells, we have shown synergism between HIV proteins and pro-atherogenic shear stress to increase endothelial cell expression of the powerful protease cathepsin K, and may implicate this protease in accelerated CVD in people living with HIV.

Aims: The aim of this study was to evaluate the effects of azilsartan (AZT) on bone loss, inflammation, and the expression of matrix metallo proteinases (MMPs), receptor activator of nuclear factor κB ligand (RANKL), receptor activator of nuclear factor κB (RANK), osteoprotegerin (OPG), cyclooxygenase-2 (COX-2), and cathepsin K in periodontal tissue in a rat model of ligature-induced periodontitis., Materials and Methods: Male Wistar albino rats were randomly divided into 5 groups of 10 rats each: (1) nonligated, water; (2) ligated, water; (3) ligated, 1 mg/kg AZT; (4) ligated, 5 mg/kg AZT; and (5) ligated, 10 mg/kg AZT. All groups were treated with saline or AZT for 10 days. Periodontal tissues were analyzed by histopathology and immunohistochemical detection of MMP-2, MMP-9, COX-2, RANKL, RANK, OPG, and cathepsin K. Levels of IL-1β, IL-10, TNF-α, myeloperoxidase (MPO), and glutathione (GSH) were determined by ELISA., Results: Treatment with 5 mg/kg AZT resulted in reduced MPO (p<0.05) and IL-1β (p<0.05), increased levels of IL-10 (p<0.05), and reduced expression of MMP-2, MMP-9, COX-2, RANK, RANKL, cathepsin K, and increased expression of OPG., Conclusions: These findings reveal that AZT increases anti-inflammatory cytokines and GSH and decreases bone loss in ligature-induced periodontitis in rats.

Background: The cysteine protease cathepsin K (CatK) has been implicated in the pathogenesis of cardiovascular disease. We sought to determine the link between atrial fibrillation (AF) and plasma CatK levels and to investigate the expression of and therapeutic target for CatK in vivo and in vitro., Methods and Results: Plasma CatK and extracellular matrix protein peptides (intact procollagen type I of N-terminal propeptide; carboxyl-terminal telopeptide of type I collagen [ICTP]) were measured in 209 consecutive patients with AF (paroxysmal AF, 146; persistent AF, 63) and 112 control subjects. In addition, the regulation of CatK expression was investigated in vivo and vitro. Patients with AF had higher plasma CatK and ICTP levels than did control subjects. Patients with persistent AF had higher levels of plasma CatK and ICTP than did patients with paroxysmal AF. CatK was correlated with ICTP concentration and left atrial diameter in all subjects. In rabbits, superoxide production, CatK activity, fibrosis, and the levels of atrial tissue angiotensin II, angiotensin type 1 receptor, gp91phox, phospho-p38 mitogen-activated protein kinase, and CatK were greater in those with tachypacing-induced AF than in controls, and these changes were reversed with angiotensin type 1 receptor antagonist. Olmesartan and mitogen-activated protein kinase inhibitor decreased the CatK expression induced by angiotensin II in rat neonatal myocytes., Conclusions: These data indicated that increased plasma CatK levels are linked with the presence of AF. Angiotensin type 1 receptor antagonist appears to be effective in alleviating atrial fibrosis in a rabbit AF model, partly reducing angiotensin type 1 receptor-p38mitogen-activated protein kinase-dependent and -independent CatK activation, thus preventing AF.

Osteoporosis is a reduction in bone mineral density (BMD). It develops less often in men than in women. This study aimed to evaluate the bone protective effects of raloxifene (RAL), risedronate (RIS), and their combination on osteoporotic male rats. Forty male Wister rats (12 weeks) were randomly divided into five groups: sham-operated group (n = 8), orchidectomized (ORX) group (n = 7), RAL group (n = 9), RIS group (n = 7) and RAL + RIS group (n = 7). RAL was orally administered at 3 mg/kg three times/week, and RIS was given subcutaneously at 5 μg/kg, twice weekly. After 6 weeks of treatment, serum cathepsin-K, alkaline (ALP) and acid phosphatase activities, serum osteocalcin, serum Ca²⁺, and Pi were determined. Urinary Ca²⁺ and deoxypyridinoline levels, BMD, and Ca²⁺ content of femur ash were estimated. Histochemical localization of ALP activity of tibia and histomorphometry was examined. As compared to sham, ORX rats showed a significant increase in bone turnover markers, and histochemical activity of ALP was increased markedly in proximal tibia of ORX rats, whereas BMD and Ca²⁺ content of femur ash were reduced after ORX. These changes were modulated after treatment with RAL and RIS or both to ORX rats; BMD of femur was improved by each treatment, and bone turnover markers were reduced as compared to ORX vehicle group. We concluded that orchidectomy induced osteoporosis and increased bone turnover in male rats because of withdrawal of sex hormones. Both RAL and RIS could treat osteoporosis in ORX rats; they reduced bone turnover markers and maintained BMD., (© 2012 The Authors Fundamental and Clinical Pharmacology © 2012 Société Française de Pharmacologie et de Thérapeutique.)

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 osteoporosis or ankylosing spondylitis., Methods: Presently there are no robust assays for the assessment of active cathepsin K in serum, and therefore an ELISA specifically detecting the N-terminal of the active form of cathepsin K was developed., Results: The assay was technically robust, with a lowest limit of detection (LOD) of 0.085 ng/mL. The average intra- and inter-assay CV% were 6.60% and 8.56% respectively. The dilution recovery and spike recovery tests in human serum were within 100±20% within the range of the assay. A comparison of latent and active cathepsin K confirmed specificity towards the active form. Quantification of the levels of active cathepsin K in supernatants of purified human osteoclasts compared to corresponding macrophages showed a 30-fold induction (p<0.001). In contrast, in serum samples from osteoporotic women on estrogen or bisphosphonate therapy and from ankylosing spondylitis patients no clinically relevant differences were observed., Conclusion: In summary, we have developed a robust and sensitive assay specifically detecting the active form of cathepsin K; however, while it monitors osteoclasts with high specificity in vitro, it appears that circulating levels of active cathepsin K do not reflect bone changes under these circumstances., (Copyright © 2013 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

Background: Cathepsin L (CatL), cathepsin K (CatK), and cathepsin V (CatV) are potent elastases implicated in human arterial wall remodeling. Whether plasma levels of these cathepsins are altered in patients with abdominal aortic aneurysms (AAAs) remains unknown., Methods and Results: Plasma samples were collected from 476 male AAA patients and 200 age-matched male controls to determine CatL, CatK, and CatV levels by ELISA. Student's t-test demonstrated significantly higher plasma CatL levels in AAA patients than in controls (P < 0.0001), whereas CatK and CatV levels were lower in AAA patients than in controls (P = 0.052, P = 0.025). ROC curve analysis confirmed higher plasma CatL levels in AAA patients than in controls (P < 0.001). As potential confounders, current smoking and use of angiotensin-converting enzyme (ACE) inhibitors, aspirin, clopidogrel, and statins associated with significantly increased plasma CatL. Pearson's correlation test demonstrated that plasma CatL associated positively with CatS (r = 0.43, P < 0.0001), body-mass index (BMI) (r = 0.07, P = 0.047) and maximal aortic diameter (r = 0.29, P < 0.001), and negatively with lowest measured ankle-brachial index (ABI) (r = -0.22, P < 0.001). Plasma CatL remained associated positively with CatS (r = 0.43, P < 0.0001) and aortic diameter (r = 0.212, P < 0.001) and negatively with ABI (r = -0.10, P = 0.011) after adjusting for the aforementioned potential confounders in a partial correlation analysis. Multivariate logistic regression analysis indicated that plasma CatL was a risk factor of AAA before (odds ratio [OR] = 3.04, P < 0.001) and after (OR = 2.42, P < 0.001) the same confounder adjustment., Conclusions: Correlation of plasma CatL levels with aortic diameter and the lowest ABI suggest that this cysteinyl protease plays a detrimental role in the pathogenesis of human peripheral arterial diseases and AAAs., (© 2013 Elsevier Ireland Ltd. All rights reserved.)

Background: Cathepsin K (CatK) is one of the most potent mammalian collagenases involved in atherosclerosis-based vascular disease. We investigated whether circulating CatK is associated with the prevalence of coronary artery disease (CAD)., Methods: Two-hundred fifty-two consecutive subjects were enrolled from among patients who underwent coronary angiography and intravascular ultrasound analyses. One-hundred thirty-two age-matched subjects served as controls. Plasma CatK, intact procollagen type I N-terminal propeptide (I-PINP), and linked carboxy-terminal telopeptide of collagen type I (ICTP) were measured., Results: Patients with CAD had higher CatK levels (44.0 ± 31.2 versus 15.5 ± 8.3 ng/mL, P < 0.001) and ICTP/I-PINP ratios (0.2 ± 0.1 versus 0.04 ± 0.03, P < 0.001) than the controls. Patients with acute coronary syndrome had higher CatK levels than those with stable angina pectoris. Overall, linear regression analysis showed that the CatK levels correlated positively with ICTP/I-PINP ratios (r = 0.41, P < 0.001). Multiple logistic regression analysis showed that CatK levels were independent predictors of CAD (odds ratio, 1.15; 95% CI, 1.07 to 1.23; P < 0.01). Furthermore, CatK levels were also correlated positively with percent plaque volumes and inversely with percent fibrous volumes by intravascular ultrasound., Conclusions: These data indicated that high levels of CatK are closely linked with the presence of CAD and that CatK serves as a novel biomarker for CAD., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Objectives: C-telopeptide crosslaps (CTX) and bone-specific alkaline phosphatase (BAP) do not provide sufficient sensitivity and specificity for diagnosis of osteoporosis. Cathepsin K (CatK), osteoprotegerin (OPG), and receptor activator of nuclear factor κB ligand (total (t) and soluble (s) RANKL) play an important role in bone metabolism. Thus serum levels of biochemical markers, each or in combination, may be useful in diagnosis of osteoporosis., Study Design: In total, 121 healthy women, 27 premenopausal women aged between 20 and 45 years, and 94 postmenopausal women aged 59-81 years, all free of known skeletal disorders were included. They underwent bone density measurement and measurement of biochemical markers., Main Outcome Measures: Based on WHO criteria, women were stratified in four groups (premenopausal: healthy; postmenopausal: healthy, osteopenia, osteoporosis), and their levels of CatK, OPG, RANKL, CTX and BAP were analyzed., Results: Using WHO criteria 21 postmenopausal women had normal bone mineral density (BMD), 49 had osteopenia and 24 had osteoporosis. There were no significant correlations of CatK, OPG and RANKL with BMD (T-score) in age-adjusted analysis, but for BAP and CTX. ROC analyses resulted in poor diagnostic validity of all parameters. The best result - also confirmed by discriminant analysis - was yielded by BAP (AUC=0.646 [0.510; 0.781]). A combination of variables did not significantly improve the diagnostic power., Conclusions: Baseline serum levels of BAP, CTX, CatK, OPG, sRANKL or tRANKL alone or in combination are not suitable to distinguish osteoporotic from non-osteoporotic postmenopausal women with sufficient accuracy., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Background: Warfarin is an anticoagulant with a narrow therapeutic index that is involved in a number of drug-drug interactions., Objectives: This study evaluates the potential effect of odanacatib (a cathepsin K inhibitor in development for the treatment of osteoporosis) on the pharmacokinetics and pharmacodynamics of warfarin., Methods: In a randomized, open-label, two-period fixed-sequence design, 13 healthy, postmenopausal female subjects received two different treatments (Treatment A: a single dose of 30 mg warfarin; Treatment B: 3 once-weekly doses of 50 mg odanacatib with 30 mg warfarin co-administered with the last dose). Warfarin R(+) and S(-) enantiomer concentrations and prothrombin time were measured at pre-dose and at specified time points over 168 hours in each treatment period. Statistical analysis was performed using linear mixed effects model., Results: Odanacatib was generally well tolerated when co-administered with warfarin in this study. The GMRs (95% confidence intervals [CI]) for plasma AUC0-∞ of warfarin+odanacatib/warfarin alone were 0.99 (0.94, 1.03) for warfarin R(+) and 1.00 (0.97, 1.03) for warfarin S(-), consistent with a lack of interaction between odanacatib and warfarin; results for Cmax, Tmax, and terminal t½ provided also demonstrated no interaction. The GMR (warfarin + odancacatib/warfarin alone) and 95% CI for the statistical comparison of INR AUC(0-168 hr) was 1.01 (0.98, 1.04)., Conclusions: The single dose pharmacokinetics and pharmacodynamics of orally administered warfarin were not meaningfully affected by multiple dose administration of odanacatib, indicating that odanacatib is not a clinically important inhibitor of CYPs 2C9, 3A4, 2C19, or 1A2.

Objectives: Cathepsin K (CatK) is expressed in high levels in osteoplasts and therefore plays an important role in bone resorption. Thus CatK serum levels may be useful in the diagnosis of chronic bone disorders such as osteopenia and osteoporosis. Therefore we aimed at studying CatK levels in women putatively free of known skeletal disorders., Study Design: In total, 121 voluntary women, 27 premenopausal women aged between 20 and 45 years, and 94 postmenopausal women aged 59-81 years, all free of known skeletal disorders were included. All women underwent bone density measurement, routine labor parameter and measurement of serum CatK levels., Main Outcome Measures: Based on WHO criteria, women were stratified in four groups (premenopausal: healthy; postmenopausal: healthy, osteopenia, osteoporosis), and their CatK levels were statistically analyzed., Results: Using WHO criteria 21 postmenopausal women had normal bone mineral density (BMD), 49 had osteopenia and 24 had osteoporosis. All 27 premenopausal women had normal BMD. There were no significant differences in CatK between these groups. ROC analysis resulted in poor diagnostic validity of CatK, where the area under curve was 0.544. There was no correlation neither between CatK and other biomarkers as C-telopeptide crosslaps (CTX) or bone-specific alkaline phosphatase (BAP) nor between CatK and age., Conclusions: Serum levels of CatK are not suitable to differentiate women with osteoporosis from healthy subjects., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Osteoporosis is a common disease among older people, especially postmenopausal women. Calcium supplementation is effective in decreasing the occurrence of osteoporosis. We tested the effect of different calcium sources (i.e., calcium carbonate chew, milk mineral chew, milk drink and placebo chew) by direct mass spectrometry (dMS) profiling and cathepsin K measurement in the serum of subjects. The dMS method is promising for plasma biomarker discovery, and cathepsin K level in the plasma is an indicator for osteoporosis. Our result shows that dMS detected characteristic ion peaks after different calcium supplement interventions; ion peak 4281.0 m/z was commonly inhibited by all three treatments. This ion peak was identified to be a fragment of follistatin-related protein 3 precursor by means of the "Lift" mode of MS/MS. The other differential ion peaks were also successfully identified: 1786.5 m/z (upregulated after calcium carbonate chew) was shown to be one fragment of transcription factor jun-B; the parent protein of 3504.7 m/z (upregulated after milk drink) was a collagen alpha-2 (type I) chain precursor; the ion peak of 3359.6 m/z (downregulated after milk mineral chew) was one fragment of family 31 glucosidase. Cathepsin K is significantly inhibited only by calcium carbonate chew treatment, indicating this form of calcium supplement has some advantage over other sources of supplementation.

The human cysteine peptidase cathepsin K is a key enzyme in bone homoeostasis and other physiological functions. In the present study we investigate the mechanism of cathepsin K action at physiological plasma pH and its regulation by modifiers that bind outside of the active site. We show that at physiological plasma pH the enzyme fluctuates between multiple conformations that are differently susceptible to macromolecular inhibitors and can be manipulated by varying the ionic strength of the medium. The behaviour of the enzyme in vitro can be described by the presence of two discrete conformations with distinctive kinetic properties and different susceptibility to inhibition by the substrate benzyloxycarbonyl-Phe-Arg-7-amino-4-methylcoumarin. We identify and characterize sulfated glycosaminoglycans as natural allosteric modifiers of cathepsin K that exploit the conformational flexibility of the enzyme to regulate its activity and stability against autoproteolysis. All sulfated glycosaminoglycans act as non-essential activators in assays using low-molecular-mass substrates. Chondroitin sulfate and dermatan sulfate bind at one site on the enzyme, whereas heparin binds at an additional site and has a strongly stabilizing effect that is unique among human glycosaminoglycans. All glycosaminoglycans stimulate the elastinolytic activity of cathepsin K at physiological plasma pH, but only heparin also increases the collagenolytic activity of the enzyme under these conditions. Altogether these results provide novel insight into the mechanism of cathepsin K function at the molecular level and its regulation in the extracellular space.

Context: Cathepsin K is a member of the cysteine protease family that cleaves both helical and telopeptide regions of collagen I, the major type of collagen in bone. Measurement of circulating levels of cathepsin K may be useful to assay the number or function of osteoclasts., Objective: The aim of the study was to evaluate the role of serum cathepsin K as a biochemical marker of bone metabolism in patients with postmenopausal osteoporosis before and after treatment with alendronate., Design, Setting and Participants: The study was a case-control and prospective study with postmenopausal osteoporotic women including a total number of 86 subjects. Serum cathepsin K was determined in 46 women with postmenopausal osteoporosis before and after 3, 6 and 12 months of treatment with alendronate. Basal serum cathepsin K levels were also compared between premenopausal healthy women (n=20), postmenopausal women without osteoporosis (n=20) and osteoporotic women. In addition, serum carboxyterminal cross-linked telopeptide of type I collagen (CTX), osteocalcin (OC) and bone-specific alkaline phosphatase (bALP) were measured., Main Outcome Measure: Changes in cathepsin K serum levels after alendronate treatment., Results: Serum cathepsin K levels were higher in postmenopausal women with osteoporosis (9.4+/-11pmol/L) compared with healthy postmenopausal women (6.8+/-8.1pmol/L; p<0.01) and premenopausal women (6.3+/-5.0pmol/L, p<0.01). Serum cathepsin K decreases gradually after alendronate treatment (17% at 3 months, 22% at 6 months and 41% at 12 months, p<0.01). In contrast, the treatment resulted in early and sustained reductions in serum CTX., Conclusion: We conclude that serum cathepsin K seems to provide additional information on bone metabolism in postmenopausal women treated with alendronate.

A pathogenic implication of cathepsin K (Cath K) and its inhibitor - cystatin C (Cyst C) occur to be of growing importance in the mechanisms of tumor invasiveness in lung cancer. This study was conducted to investigate the prognostic role and the effects of chemotherapy on serum Cath K and Cyst C (ELISA) in patients with advanced stage non-small cell lung cancer (NSCLC). The study entered 40 patients (32 men) and 15 healthy volunteers (control group). Peripheral blood samples were taken before and after four cycles of chemotherapy. The mean serum Cyst C levels were significantly higher in patients with advanced NSCLC than in controls (p=0.003). The levels of Cath K in serum of NSCLC are comparable to those in controls. No correlation was found between Cath K and Cyst C concentrations and the histological type and staging of lung cancer. Patients with T4-stage had a lower level of Cyst C, than those with T2 (p=0.033). No correlation was found between the concentrations of Cath K, Cyst C and the effect of chemotherapy. However, Cyst C level positively correlated with serum creatinine concentration (R=0.535; p=0.005) in patients who responded to chemotherapy and with patient's age (R=0.456; p=0.018) in whole group. When the cut-off values of serum Cath K and Cyst C (23.35 pmol/l, 1.29 mg/l, respectively) were used, the prognoses of high and low groups were not different. Concluding, patients with lung cancer have a higher serum concentration of Cyst C compared to healthy people. In our opinion, determination of Cath K and Cyst C concentrations has no clinical significance in the prognosis of the survival time in lung cancer.