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Human xylosyltransferases--mediators of arthrofibrosis? New pathomechanistic insights into arthrofibrotic remodeling after knee replacement therapy.

ABSTRACT: Total knee replacement (TKR) is a common therapeutic option to restore joint functionality in chronic inflammatory joint diseases. Subsequent arthrofibrotic remodeling occurs in 10%, but the underlying pathomechanisms remain unclear. We evaluated the association of xylosyltransferases (XT), fibrotic mediators catalyzing glycosaminoglycan biosynthesis, leading to arthrofibrosis as well as the feasibility of using serum XT activity as a diagnostic marker. For this purpose, synovial fibroblasts (SF) were isolated from arthrofibrotic and control synovial biopsies. Basal α-smooth muscle actin expression revealed a high fibroblast-myofibroblast transition rate in arthrofibrotic fibroblasts. Fibrotic remodeling marked by enhanced XT activity, α-SMA protein expression as well as xylosyltransferase-I, collagen type III-alpha-1 and ACTA2 mRNA expression was stronger in arthrofibrotic than in control fibroblasts treated with transforming growth factor-β1 (TGF-β1). Otherwise, no differences between serum levels of XT-I activity or common fibrosis markers (galectin-3 and growth differentiation factor-15 levels (GDF-15)) were found between 95 patients with arthrofibrosis and 132 controls after TKR. In summary, XT-I was initially investigated as a key cellular mediator of arthrofibrosis and a target for therapeutic intervention. However, the blood-synovial-barrier makes arthrofibrotic molecular changes undetectable in serum. Future studies on monitoring or preventing arthrofibrotic remodeling should therefore rely on local instead of systemic parameters.

SUBMITTER: Faust I

PROVIDER: S-EPMC4517395 | biostudies-other | 2015

REPOSITORIES: biostudies-other

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Project description:BackgroundTotal hip or knee arthroplasties (THA/TKA) show favorable long-term effects, yet the recovery process may take weeks to months. Physical therapy (PT) following discharge from hospital is an effective intervention to enhance this recovery process. To investigate the relation between recovery and postoperative PT usage, including the presence of comorbidities, 6 months after THA/TKA.MethodsMulticenter, observational study in primary THA/TKA patients who completed preoperative and 6 months postoperative assessments. The assessments included questions on PT use (yes/no and duration; long term use defined as ≥ 12 weeks), comorbidities (musculoskeletal, non-musculoskeletal, sensory comorbidities and frequency of comorbidities). Recovery was assessed with the HOOS/KOOS on all 5 subdomains. Logistic regression with long term PT as outcome was performed adjusted for confounding including an interaction term (comorbidity*HOOS/KOOS-subdomain).ResultsIn total, 1289 THA and 1333 TKA patients were included, of whom 95% received postoperative PT, 56% and 67% received postoperative PT ≥ 12 weeks respectively. In both THA and TKA group, less improvement on all HOOS/KOOS domain scores was associated with ≥ 12 weeks of postoperative PT (range Odds Ratios 0.97-0.99). In the THA group the impact of recovery was smaller in patient with comorbidities as non- musculoskeletal comorbidities modified all associations between recovery and postoperative PT duration (Odds Ratios range 1.01-1.05). Musculoskeletal comorbidities modified the associations between Function-in-Daily-Living-and Sport-and-recreation recovery and postoperative PT. Sensory comorbidities only had an effect on Sport-and-recreation recovery and postoperative PT. Also the frequency of comorbidities modified the relation between Function-in-Daily-Living, pain and symptoms recovery and postoperative PT. In the TKA group comorbidity did not modify the associations.ConclusionWorse recovery was associated with longer duration of postoperative PT suggesting that PT provision is in line with patients' needs. The impact of physical recovery on the use of long-term postoperative PT was smaller in THA patients with comorbidities.Trial registrationRegistered in the Dutch Trial Registry on March 13, 2012. TRIAL ID NTR3348; registration number: P12.047. https://www.trialregister.nl/trial/3197 .

Project description:ImportanceMany individuals who undergo total knee replacement (TKR) become long-term opioid users after TKR. Associations of physical therapy (PT) interventions before or after TKR with long-term use of opioids are not known.ObjectivesTo evaluate associations of PT interventions before and after TKR with long-term opioid use after TKR.Design, setting, and participantsThis cohort study used data from the OptumLabs Data Warehouse on 67 322 individuals aged 40 years or older who underwent TKR from January 1, 2001, to December 31, 2016, stratified by history of opioid use. The analyses for the study included data from January 1, 1999, to December 31, 2018.ExposuresAny PT interventions within 90 days before or after TKR, post-TKR PT dose as number of sessions (ie, 1-5, 6-12, and ≥13 sessions), post-TKR PT timing as number of days to initiation of care (ie, <30 days, 31-60 days, or 61-90 days after TKR), and post-TKR PT type (ie, active vs passive).Main outcomes and measuresThe association of pre- and post-TKR PT with risk of long-term opioid use occurring more than 90 days after TKR was assessed using logistic regression while adjusting for confounders, including age, sex, race and ethnicity (Asian, Black, Hispanic, or White), obesity, type of insurance, geographical location, and physical and mental health comorbidities.ResultsA total of 38 408 opioid-naive individuals (21 336 women [55.6%]; mean [SD] age, 66.2 [9.2] years) and 28 914 opioid-experienced individuals (18 426 women [63.7%]; mean [SD] age, 64.4 [9.3] years) were included. Receipt of any PT before TKR was associated with lower odds of long-term opioid use in the opioid-naive (adjusted odds ratio [aOR], 0.75 [95% CI, 0.60-0.95]) and opioid-experienced (aOR, 0.75 [95% CI, 0.70-0.80]) cohorts. Receipt of any post-TKR PT was associated with lower odds of long-term use of opioids in the opioid-experienced cohort (aOR, 0.75 [95% CI, 0.70-0.79]). Compared with 1 to 5 sessions of PT after TKR, 6 to 12 sessions (aOR, 0.82 [95% CI, 0.75-0.90]) and 13 or more sessions (aOR, 0.71 [95% CI, 0.65-0.77) were associated with lower odds in the opioid-experienced cohort. Compared with initiation of PT within 30 days after TKR, initiation 31 to 60 days or 61 to 90 days after TKR were associated with greater odds in the opioid-naive (31-60 days: aOR, 1.45 [95% CI, 1.19-1.77]; 61-90 days: aOR, 2.15 [95% CI, 1.43-3.22]) and opioid-experienced (31-60 days: aOR, 1.10 [95% CI, 1.02-1.18]; 61-90 days: aOR, 1.32 [95% CI, 1.12-1.55]) cohorts. Compared with passive PT, active PT was not associated with long-term opioid use in the opioid-naive (aOR, 1.00 [95% CI, 0.81-1.24]) or opioid-experienced (aOR, 0.99 [95% CI, 0.92-1.07]) cohorts.Conclusions and relevanceThis cohort study suggests that receipt of PT intervention before and after TKR, receipt of 6 or more sessions of PT care after TKR, and initiation of PT care within 30 days after TKR were associated with lower odds of long-term opioid use. These findings suggest that PT may help reduce the risk of long-term opioid use after TKR.

Project description:Cathepsin D (CatD) is a lysosomal aspartyl endopeptidase originally considered a "house keeping enzyme" involved in the clearance of unwanted proteins. However, recent studies have revealed CatD's involvement in apoptosis and autophagy, thus signifying an important function in the proper development and maintenance of multi-cellular organs. In the mammary gland, matrix degradation and the remodeling process are orchestrated by proteolytic enzymes, but the role of CatD at distinct developmental stages has remained mostly unexplored. Based on our previous studies we sought to address the role of this endopeptidase in mammary gland development and remodeling. By employing a mouse model, we report a previously unidentified participation of CatD in different stages of mammary gland development. Our findings reveal that CatD undergoes distinct protein processing at different stages of mammary gland development, and this customized processing results in differential enzymatic activity (constitutive and low pH activatable) best fitting particular stage(s) of development. In addition, at the onset of involution the N-glycan structure of this endopeptidase switches from a mixed high mannose and hybrid structure to an almost exclusively high mannose type, but reverts back to the original N-glycan composition by day 4 of involution. Our findings illuminate (at least in part) the "raison d'être" for CatD's numerous and highly regulated proteolytic processing steps from the pro-form to the mature enzyme. In the mammary gland, specific cleavage product(s) perform specialized function(s) befitting each stage of remodeling. It is noteworthy that deregulated synthesis, secretion and glycosylation of CatD are hallmarks of cancer progression. Thus, identifying the role of CatD in a dynamic normal tissue undergoing highly regulated cycles of remodeling could provide valuable information illuminating the deregulation of CatD associated with cancer development and metastasis.

Project description:BACKGROUND:Nicotine, the pharmacologically active substance in both tobacco and many electronic cigarette (e-cigarette) liquids, is responsible for the addiction that sustains cigarette smoking. With 8 million deaths worldwide annually, smoking remains one of the major causes of disability and premature death. However, nicotine also plays an important role in smoking cessation strategies. OBJECTIVES:The aim of this study was to develop a comprehensive, whole-body, physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) model of nicotine and its major metabolite cotinine, covering various routes of nicotine administration, and to simulate nicotine brain tissue concentrations after the use of combustible cigarettes, e-cigarettes, nicotine gums, and nicotine patches. METHODS:A parent-metabolite, PBPK/PD model of nicotine for a non-smoking and a smoking population was developed using 91 plasma and brain tissue concentration-time profiles and 11 heart rate profiles. Among others, cytochrome P450 (CYP) 2A6 and 2B6 enzymes were implemented, including kinetics for CYP2A6 poor metabolizers. RESULTS:The model is able to precisely describe and predict both nicotine plasma and brain tissue concentrations, cotinine plasma concentrations, and heart rate profiles. 100% of the predicted area under the concentration-time curve (AUC) and maximum concentration (Cmax) values meet the twofold acceptance criterion with overall geometric mean fold errors of 1.12 and 1.15, respectively. The administration of combustible cigarettes, e-cigarettes, nicotine patches, and nicotine gums was successfully implemented in the model and used to identify differences in steady-state nicotine brain tissue concentration patterns. CONCLUSIONS:Our PBPK/PD model may be helpful in further investigations of nicotine dependence and smoking cessation strategies. As the model represents the first nicotine PBPK/PD model predicting nicotine concentration and heart rate profiles after the use of e-cigarettes, it could also contribute to a better understanding of the recent increase in youth e-cigarette use.

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Human xylosyltransferases--mediators of arthrofibrosis? New pathomechanistic insights into arthrofibrotic remodeling after knee replacement therapy.

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