Autoantibodies binding to citrullinated telopeptide of type II collagen and to cyclic citrullinat... more Autoantibodies binding to citrullinated telopeptide of type II collagen and to cyclic citrullinated peptides predict synergistically the development of seropositive rheumatoid arthritis
Background: Various indexes have been developed to estimate the risk for mortality, institutional... more Background: Various indexes have been developed to estimate the risk for mortality, institutionalization, and other adverse outcomes for older people. Most indexes are based on a large number of clinical or laboratory parameters. An index based on only a few parameters would be more practical to use in every-day clinical practice.Methods: A prospective study with a 10-year follow-up period. Thirty-six clinical and fourteen laboratory parameters were combined to form an index. Cox regression model was used to analyze the association of the index with institutionalization and mortality. A backward statistical method was used to reduce the number of parameters to form an easy-to-use index for predicting institutionalization and mortality.Results: The mean age of the participants (n=1172) was 73.1 (SD 6.6, range 64‒97) years. Altogether, 149 (14%) subjects were institutionalized, and 413 (35%) subjects deceased during the follow-up. Institutionalization and mortality rates increased as ...
between total and intact assays for N-terminal propeptide of type I procollagen reflects degradat... more between total and intact assays for N-terminal propeptide of type I procollagen reflects degradation of pN-collagen rather than denaturation of intact propeptide
Background Previously, several indexes based on a large number of clinical and laboratory tests t... more Background Previously, several indexes based on a large number of clinical and laboratory tests to predict mortality and frailty have been produced. However, there is still a need for an easily applicable screening tool for every-day clinical practice. Methods A prospective study with 10- and 18-year follow-ups. Fourteen common laboratory tests were combined to an index. Cox regression model was used to analyse the association of the laboratory index with institutionalization and mortality. Results The mean age of the participants (n = 1153) was 73.6 (SD 6.8, range 64.0–100.0) years. Altogether, 151 (14.8%) and 305 (29.9%) subjects were institutionalized and 422 (36.6%) and 806 (69.9%) subjects deceased during the 10- and 18-year follow-ups, respectively. Higher LI (laboratory index) scores predicted increased mortality. Mortality rates increased as LI scores increased both in unadjusted and in age- and gender-adjusted models during both follow-ups. The LI did not significantly pred...
The specificities and cross-reactions of antibodies induced by citrulline- and homocitrulline-con... more The specificities and cross-reactions of antibodies induced by citrulline- and homocitrulline-containing proteins may give implications on the role of citrulline- and homocitrulline-binding antibodies in the pathogenesis and progression of rheumatoid arthritis (RA). Here we use rabbits as an experimental model of antibody development in RA. Thirty-two animals were immunized with peptide antigens containing either homocitrulline or citrulline. The sera were tested for binding to CCP and MCV antigens and to peptide sequences related to carboxyterminal telopeptides of type I and II collagens and containing arginine, citrulline, or homocitrulline. The binding of CCP and MCV antigens to antisera against homocitrulline-containing immunogens could be inhibited by human serum albumin containing homocitrulline, whereas similar binding to sera against citrulline-containing immunogens was not inhibited. The antisera induced with citrulline-containing collagen telopeptides recognized type I collagen-related antigens in a sequence-specific manner, as antibody binding to both citrulline- and homocitrulline-containing peptides was inhibited by corresponding citrullinated and native peptides. In contrast, type II collagen-related peptides were recognized by the antisera in a ureido group-specific manner, as their binding to homocitrulline-containing peptide was inhibited by both citrulline- and homocitrulline-containing, but not native peptide. Binding of the citrullinated type II collagen peptide could only be inhibited by the similarly citrullinated peptide. In conclusion, antibodies induced with citrulline or homocitrulline-containing antigens bound antigens in a ureido group-specific manner, recognizing citrulline and homocitrulline also in other sequences than those used in the original immunization. In competitive situations the amino acid present in the immunization antigen was favored.
Protein Deimination in Human Health and Disease, 2013
A structural homolog to citrulline, homocitrulline, can be present in proteins and peptides as a ... more A structural homolog to citrulline, homocitrulline, can be present in proteins and peptides as a product of posttranslational modification. Homocitrulline is formed nonenzymatically from lysine residues in the polypeptide chain by the action of cyanate. The latter compound is derived either from urea or, via a reaction catalyzed by the enzyme myeloperoxidase (MPO), from thiocyanate. The formation of homocitrulline is known as carbamoylation or carbamylation. In humans, this process takes place predominantly in two types of situations: uremia and inflammation. Smoking increases the circulating thiocyanate concentration and thus enhances carbamoylation of proteins.
IntroductionOur objective was to find out if there are antibodies binding to homocitrulline-conta... more IntroductionOur objective was to find out if there are antibodies binding to homocitrulline-containing type I and II collagen carboxyterminal telopeptides in sera of patients with rheumatoid arthritis (RA), and if these antibodies cross-react with citrulline and homocitrulline in the same peptide sequence.MethodsA total of 72 RA and 72 control sera were analyzed for binding using enzyme-linked immunosorbent assay to citrulline- or homocitrulline-containing type I and II collagen carboxyterminal telopeptides, as well as to cyclic citrullinated peptide (CCP) and to mutated citrullinated vimentin (MCV). Specificities of the antibodies were tested using inhibition-ELISA.ResultsOf the RA sera, 39 (54 %) and 41 (57 %) were positive for binding to CCP and MCV, respectively. Further, 34 (47%) and 30 (42%) of the patients had specific antibodies binding to and being inhibited by citrulline-containing type I collagen telopeptides and by citrulline-containing type II collagen carboxyterminal t...
The synthesis rates of fibrillar collagens can be assessed in blood by measuring propeptides set ... more The synthesis rates of fibrillar collagens can be assessed in blood by measuring propeptides set free from corresponding procollagens before fiber formation. Type I collagen is the major component of the organic matrix of bone, but it is also found in other connective tissues. The serum concentration of the amino-terminal propeptide of type I procollagen, PINP, functions as a measure of type I collagen synthesis during normal bone turnover, but it is also released from bone metastases that involve an osteoblastic component. Type III collagen is a major constituent of soft tissues and the corresponding amino-terminal propeptide, PIIINP, reflects collagen synthesis. Circulating PIIINP tends to be affected by malignomas that grow in the peritoneal cavity or affect bone marrow. Many studies on procollagen markers in cancer have been cross-sectional or demonstrated treatment effects in patient groups. Markers that originate from bone turnover have wide reference intervals, but low biologic variability in individuals. Thus, they appear better suited for monitoring versus diagnostic purposes. There is still definite need for research on the use of procollagen markers in the followup of individual patients undergoing cancer treatment or being monitored after such treatment.
Citrulline formation through the deimination of arginine residues has recently been identified as... more Citrulline formation through the deimination of arginine residues has recently been identified as an enzymatic post-translational modification of proteins that could be related to breaking the tolerance to self-antigens in the development of rheumatoid arthritis. Autoantibodies recognizing citrullinated peptides are highly specific indicators of early rheumatoid arthritis. However, current knowledge of the natural proteins that are citrullinated does not explain the main manifestations of the disease, that is, progressive damage to cartilage and bone - tissues rich in extracellular matrix. Several collagen types are present in the joint, where they provide the structural scaffold of the tissues. Recent findings indicate that both the ubiquitous Type I collagen and the cartilage-specific Type II collagen can be enzymatically citrullinated in vitro. Synthetic citrullinated peptides related to collagen sequences can be used as antigens. Autoantibodies to these citrullinated forms are found in patients with early rheumatoid arthritis. This review summarizes what is known regarding the occurrence of citrulline in a major class of extracellular matrix proteins, the fibrillar collagens and the significance of autoantibodies to citrulline in these proteins.
We developed sensitive assay methods for autoantibodies recognizing the citrullinated synthetic p... more We developed sensitive assay methods for autoantibodies recognizing the citrullinated synthetic peptides derived from type I and type II collagens in patients with rheumatoid arthritis (RA). These peptides were tested with the chemiluminescence method (Nichols Advantage
N-terminal propeptide of type I procollagen assay (PINP) reflects the rate of type I collagen syn... more N-terminal propeptide of type I procollagen assay (PINP) reflects the rate of type I collagen synthesis Different sera were fractioned by gel filtration and analyzed with intact and total PINP assays. The sizes of the antigens were determined by western blotting. The thermal stability was tested at +37°C, +4°C and room temperature (RT). Automated intact PINP assay hardly measured monomeric form. In haemodialysis patients intact and total PINP assays gave significantly different results. The monomeric PINP antigen in serum was larger than the trimeric PINP antigen. PINP were thermally stable at least 7 days at +4°C and at RT but the results of both assays were decreased similarly at +37°C. The IDS-iSYS intact PINP assay is precise and sensitive. It seems that monomeric form is not derived from the thermal instability of the trimers but acts as a confounding factor.
High dietary phosphorus (P) intake has acute negative effects on calcium (Ca) and bone metabolism... more High dietary phosphorus (P) intake has acute negative effects on calcium (Ca) and bone metabolism, but long-term clinical data are contradictory. We hypothesized that high P intake is associated with impaired bone health as suggested by earlier short-term studies on bone metabolism. In this cross-sectional study, we investigated associations between dietary P intake, bone traits in the radius and tibia, and bone turnover in a population-based sample of 37- to 47-year-old Caucasian premenopausal women (n=333) and men (n=179) living in Southern Finland (60°N). We used various regression models in an "elaboration approach" to elucidate the role of P intake in bone traits and turnover. The addition of relevant covariates to the models mainly removed the significance of P intake as a determinant of bone traits. In the final regression model (P intake, weight, height, age, Ca intake, serum 25-hydroxyvitamin D, physical activity, smoking, contraceptive use in women), P intake was...
Autoantibodies binding to citrullinated telopeptide of type II collagen and to cyclic citrullinat... more Autoantibodies binding to citrullinated telopeptide of type II collagen and to cyclic citrullinated peptides predict synergistically the development of seropositive rheumatoid arthritis
Background: Various indexes have been developed to estimate the risk for mortality, institutional... more Background: Various indexes have been developed to estimate the risk for mortality, institutionalization, and other adverse outcomes for older people. Most indexes are based on a large number of clinical or laboratory parameters. An index based on only a few parameters would be more practical to use in every-day clinical practice.Methods: A prospective study with a 10-year follow-up period. Thirty-six clinical and fourteen laboratory parameters were combined to form an index. Cox regression model was used to analyze the association of the index with institutionalization and mortality. A backward statistical method was used to reduce the number of parameters to form an easy-to-use index for predicting institutionalization and mortality.Results: The mean age of the participants (n=1172) was 73.1 (SD 6.6, range 64‒97) years. Altogether, 149 (14%) subjects were institutionalized, and 413 (35%) subjects deceased during the follow-up. Institutionalization and mortality rates increased as ...
between total and intact assays for N-terminal propeptide of type I procollagen reflects degradat... more between total and intact assays for N-terminal propeptide of type I procollagen reflects degradation of pN-collagen rather than denaturation of intact propeptide
Background Previously, several indexes based on a large number of clinical and laboratory tests t... more Background Previously, several indexes based on a large number of clinical and laboratory tests to predict mortality and frailty have been produced. However, there is still a need for an easily applicable screening tool for every-day clinical practice. Methods A prospective study with 10- and 18-year follow-ups. Fourteen common laboratory tests were combined to an index. Cox regression model was used to analyse the association of the laboratory index with institutionalization and mortality. Results The mean age of the participants (n = 1153) was 73.6 (SD 6.8, range 64.0–100.0) years. Altogether, 151 (14.8%) and 305 (29.9%) subjects were institutionalized and 422 (36.6%) and 806 (69.9%) subjects deceased during the 10- and 18-year follow-ups, respectively. Higher LI (laboratory index) scores predicted increased mortality. Mortality rates increased as LI scores increased both in unadjusted and in age- and gender-adjusted models during both follow-ups. The LI did not significantly pred...
The specificities and cross-reactions of antibodies induced by citrulline- and homocitrulline-con... more The specificities and cross-reactions of antibodies induced by citrulline- and homocitrulline-containing proteins may give implications on the role of citrulline- and homocitrulline-binding antibodies in the pathogenesis and progression of rheumatoid arthritis (RA). Here we use rabbits as an experimental model of antibody development in RA. Thirty-two animals were immunized with peptide antigens containing either homocitrulline or citrulline. The sera were tested for binding to CCP and MCV antigens and to peptide sequences related to carboxyterminal telopeptides of type I and II collagens and containing arginine, citrulline, or homocitrulline. The binding of CCP and MCV antigens to antisera against homocitrulline-containing immunogens could be inhibited by human serum albumin containing homocitrulline, whereas similar binding to sera against citrulline-containing immunogens was not inhibited. The antisera induced with citrulline-containing collagen telopeptides recognized type I collagen-related antigens in a sequence-specific manner, as antibody binding to both citrulline- and homocitrulline-containing peptides was inhibited by corresponding citrullinated and native peptides. In contrast, type II collagen-related peptides were recognized by the antisera in a ureido group-specific manner, as their binding to homocitrulline-containing peptide was inhibited by both citrulline- and homocitrulline-containing, but not native peptide. Binding of the citrullinated type II collagen peptide could only be inhibited by the similarly citrullinated peptide. In conclusion, antibodies induced with citrulline or homocitrulline-containing antigens bound antigens in a ureido group-specific manner, recognizing citrulline and homocitrulline also in other sequences than those used in the original immunization. In competitive situations the amino acid present in the immunization antigen was favored.
Protein Deimination in Human Health and Disease, 2013
A structural homolog to citrulline, homocitrulline, can be present in proteins and peptides as a ... more A structural homolog to citrulline, homocitrulline, can be present in proteins and peptides as a product of posttranslational modification. Homocitrulline is formed nonenzymatically from lysine residues in the polypeptide chain by the action of cyanate. The latter compound is derived either from urea or, via a reaction catalyzed by the enzyme myeloperoxidase (MPO), from thiocyanate. The formation of homocitrulline is known as carbamoylation or carbamylation. In humans, this process takes place predominantly in two types of situations: uremia and inflammation. Smoking increases the circulating thiocyanate concentration and thus enhances carbamoylation of proteins.
IntroductionOur objective was to find out if there are antibodies binding to homocitrulline-conta... more IntroductionOur objective was to find out if there are antibodies binding to homocitrulline-containing type I and II collagen carboxyterminal telopeptides in sera of patients with rheumatoid arthritis (RA), and if these antibodies cross-react with citrulline and homocitrulline in the same peptide sequence.MethodsA total of 72 RA and 72 control sera were analyzed for binding using enzyme-linked immunosorbent assay to citrulline- or homocitrulline-containing type I and II collagen carboxyterminal telopeptides, as well as to cyclic citrullinated peptide (CCP) and to mutated citrullinated vimentin (MCV). Specificities of the antibodies were tested using inhibition-ELISA.ResultsOf the RA sera, 39 (54 %) and 41 (57 %) were positive for binding to CCP and MCV, respectively. Further, 34 (47%) and 30 (42%) of the patients had specific antibodies binding to and being inhibited by citrulline-containing type I collagen telopeptides and by citrulline-containing type II collagen carboxyterminal t...
The synthesis rates of fibrillar collagens can be assessed in blood by measuring propeptides set ... more The synthesis rates of fibrillar collagens can be assessed in blood by measuring propeptides set free from corresponding procollagens before fiber formation. Type I collagen is the major component of the organic matrix of bone, but it is also found in other connective tissues. The serum concentration of the amino-terminal propeptide of type I procollagen, PINP, functions as a measure of type I collagen synthesis during normal bone turnover, but it is also released from bone metastases that involve an osteoblastic component. Type III collagen is a major constituent of soft tissues and the corresponding amino-terminal propeptide, PIIINP, reflects collagen synthesis. Circulating PIIINP tends to be affected by malignomas that grow in the peritoneal cavity or affect bone marrow. Many studies on procollagen markers in cancer have been cross-sectional or demonstrated treatment effects in patient groups. Markers that originate from bone turnover have wide reference intervals, but low biologic variability in individuals. Thus, they appear better suited for monitoring versus diagnostic purposes. There is still definite need for research on the use of procollagen markers in the followup of individual patients undergoing cancer treatment or being monitored after such treatment.
Citrulline formation through the deimination of arginine residues has recently been identified as... more Citrulline formation through the deimination of arginine residues has recently been identified as an enzymatic post-translational modification of proteins that could be related to breaking the tolerance to self-antigens in the development of rheumatoid arthritis. Autoantibodies recognizing citrullinated peptides are highly specific indicators of early rheumatoid arthritis. However, current knowledge of the natural proteins that are citrullinated does not explain the main manifestations of the disease, that is, progressive damage to cartilage and bone - tissues rich in extracellular matrix. Several collagen types are present in the joint, where they provide the structural scaffold of the tissues. Recent findings indicate that both the ubiquitous Type I collagen and the cartilage-specific Type II collagen can be enzymatically citrullinated in vitro. Synthetic citrullinated peptides related to collagen sequences can be used as antigens. Autoantibodies to these citrullinated forms are found in patients with early rheumatoid arthritis. This review summarizes what is known regarding the occurrence of citrulline in a major class of extracellular matrix proteins, the fibrillar collagens and the significance of autoantibodies to citrulline in these proteins.
We developed sensitive assay methods for autoantibodies recognizing the citrullinated synthetic p... more We developed sensitive assay methods for autoantibodies recognizing the citrullinated synthetic peptides derived from type I and type II collagens in patients with rheumatoid arthritis (RA). These peptides were tested with the chemiluminescence method (Nichols Advantage
N-terminal propeptide of type I procollagen assay (PINP) reflects the rate of type I collagen syn... more N-terminal propeptide of type I procollagen assay (PINP) reflects the rate of type I collagen synthesis Different sera were fractioned by gel filtration and analyzed with intact and total PINP assays. The sizes of the antigens were determined by western blotting. The thermal stability was tested at +37°C, +4°C and room temperature (RT). Automated intact PINP assay hardly measured monomeric form. In haemodialysis patients intact and total PINP assays gave significantly different results. The monomeric PINP antigen in serum was larger than the trimeric PINP antigen. PINP were thermally stable at least 7 days at +4°C and at RT but the results of both assays were decreased similarly at +37°C. The IDS-iSYS intact PINP assay is precise and sensitive. It seems that monomeric form is not derived from the thermal instability of the trimers but acts as a confounding factor.
High dietary phosphorus (P) intake has acute negative effects on calcium (Ca) and bone metabolism... more High dietary phosphorus (P) intake has acute negative effects on calcium (Ca) and bone metabolism, but long-term clinical data are contradictory. We hypothesized that high P intake is associated with impaired bone health as suggested by earlier short-term studies on bone metabolism. In this cross-sectional study, we investigated associations between dietary P intake, bone traits in the radius and tibia, and bone turnover in a population-based sample of 37- to 47-year-old Caucasian premenopausal women (n=333) and men (n=179) living in Southern Finland (60°N). We used various regression models in an "elaboration approach" to elucidate the role of P intake in bone traits and turnover. The addition of relevant covariates to the models mainly removed the significance of P intake as a determinant of bone traits. In the final regression model (P intake, weight, height, age, Ca intake, serum 25-hydroxyvitamin D, physical activity, smoking, contraceptive use in women), P intake was...
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