In vitro collagen biomarkers in mechanically stimulated human tendon cells: a systematic review.

OBJECTIVE: The aim of this study was to comprehensively examine and summarize the available in vitro evidence regarding the relationship between mechanical stimulation and biomarkers of collagen synthesis in human-derived tendon cells. METHODS: Systematic review with narrative analyses and risk of bias assessment guided by the Health Assessment and Translation tool. The electronic databases MEDLINE (Ovid), EMBASE (Ovid), CENTRAL (Ovid) and COMPENDEX (Engineering Village) were systematically searched from inception to 3 August 2023. Inclusion criteria encompassed English language, original experimental, or quasi-experimental in vitro publications that subjected human tendon cells to mechanical stimulation, with collagen synthesis (total collagen, type I, III, V, XI, XII, and XIV) and related biomarkers (matrix metalloproteinases, transforming growth factor ß, scleraxis, basic fibroblast growth factor) as outcomes. RESULTS: Twenty-one publications were included. A pervasive definite high risk of bias was evident in all included studies. Owing to incomplete outcome reporting and heterogeneity in mechanical stimulation protocols, planned meta-analyses were unfeasible. Reviewed data suggested that human tendon cells respond to mechanical stimulation with increased synthesis of collagen (e.g., COL1A1, procollagen, total soluble collagen, etc.), scleraxis and several matrix metalloproteinases. Results also indicate that mechanical stimulation dose magnitude may influence synthesis in several biomarkers. CONCLUSIONS: A limited number of studies, unfortunately characterized by a definite high risk of bias, suggest that in vitro mechanical stimulation primarily increases type I collagen synthesis by human tendon cells. Findings from this systematic review provide researchers and clinicians with biological evidence concerning the possible beneficial influence of exercise and loading on cellular-level tendon adaptation.

Combined hormonal contraceptive use is not protective against musculoskeletal conditions or injuries: a systematic review with data from 5 million females.

OBJECTIVE: Assess the association between combined hormonal contraceptives (CHC) use and musculoskeletal tissue pathophysiology, injuries or conditions. DESIGN: Systematic review with semiquantitative analyses and certainty of evidence assessment, guided by the Grading of Recommendations Assessment, Development and Evaluation approach. DATA SOURCES: MEDLINE, EMBASE, CENTRAL, SPORTDiscus, CINAHL searched from inception to April 2022. ELIGIBILITY: Intervention and cohort studies that assessed the association between new or ongoing use of CHC and an outcome of musculoskeletal tissue pathophysiology, injury or condition in postpubertal premenopausal females. RESULTS: Across 50 included studies, we assessed the effect of CHC use on 30 unique musculoskeletal outcomes (75% bone related). Serious risk of bias was judged present in 82% of studies, with 52% adequately adjusting for confounding. Meta-analyses were not possible due to poor outcome reporting, and heterogeneity in estimate statistics and comparison conditions. Based on semiquantitative synthesis, there is low certainty evidence that CHC use was associated with elevated future fracture risk (risk ratio 1.02-1.20) and total knee arthroplasty (risk ratio 1.00-1.36). There is very low certainty evidence of unclear relationships between CHC use and a wide range of bone turnover and bone health outcomes. Evidence about the effect of CHC use on musculoskeletal tissues beyond bone, and the influence of CHC use in adolescence versus adulthood, is limited. CONCLUSION: Given a paucity of high certainty evidence that CHC use is protective against musculoskeletal pathophysiology, injury or conditions, it is premature and inappropriate to advocate, or prescribe CHC for these purposes. PROSPERO REGISTRATION NUMBER: This review was registered on PROSPERO CRD42021224582 on 8 January 2021.

The effects of cholesterol accumulation on Achilles tendon biomechanics: A cross-sectional study.

Familial hypercholesterolemia, a common genetic metabolic disorder characterized by high cholesterol levels, is involved in the development of atherosclerosis and other preventable diseases. Familial hypercholesterolemia can also cause tendinous abnormalities, such as thickening and xanthoma (tendon lipid accumulation) in the Achilles, which may impede tendon biomechanics. The objective of this study was to investigate the effect of cholesterol accumulation on the biomechanical performance of Achilles tendons, in vivo. 16 participants (10 men, 6 women; 37±6 years) with familial hypercholesterolemia, diagnosed with tendon xanthoma, and 16 controls (10 men, 6 women; 36±7 years) underwent Achilles biomechanical assessment. Achilles biomechanical data was obtained during preferred pace, shod, walking by analysis of lower limb kinematics and kinetics utilizing 3D motion capture and an instrumented treadmill. Gastrocnemius medialis muscle-tendon junction displacement was imaged using ultrasonography. Achilles stiffness, hysteresis, strain and force were calculated from displacement-force data acquired during loading cycles, and tested for statistical differences using one-way ANOVA. Statistical parametric mapping was used to examine group differences in temporal data. Participants with familial hypercholesterolemia displayed lower Achilles stiffness compared to the control group (familial hypercholesterolemia group: 87±20 N/mm; controls: 111±18 N/mm; p = 0.001), which appeared to be linked to Achilles loading rate rather than an increased strain (FH: 5.27±1.2%; controls: 4.95±0.9%; p = 0.413). We found different Achilles loading patterns in the familial hypercholesterolemia group, which were traced to differences in the centre of pressure progression that affected ankle moment. This finding may indicate that individuals with familial hypercholesterolemia use different Achilles loading strategies. Participants with familial hypercholesterolemia also demonstrated significantly greater Achilles hysteresis than the control group (familial hypercholesterolemia: 57.5±7.3%; controls: 43.8±10%; p<0.001), suggesting that walking may require a greater metabolic cost. Our results indicate that cholesterol accumulation could contribute to reduced Achilles function, while potentially increasing the chance of injury.

Diagnostic accuracy of ultrasound and MRI for Achilles tendon xanthoma in people with familial hypercholesterolemia: A systematic review.

BACKGROUND: Achilles tendon xanthoma (ATX) results from tendon thickening and subclinical inflammation triggered by hypercholesterolemia, and is associated with more severe coronary artery disease and a higher risk of cardiovascular events. The ability to detect ATX by clinical examination is limited, and diagnostic imaging, for instance, using ultrasonography or magnetic resonance imagine (MRI), may improve the identification of ATX. However, the accuracy of ultrasound (US) imaging or MRI in identifying ATX in people with familial hypercholesterolemia (FH) has not been systematically reviewed. OBJECTIVE: The objective of this study was to systematically review the accuracy of US imaging or MRI in diagnosing ATX in individuals with FH. METHODS: Searches in Medline, Embase, Cochrane Central, and Cochrane Database of Systematic Reviews on the Ovid platform from inception to April 15, 2018, were conducted to identify articles. Any study design that included US imaging or MRI of Achilles tendon xanthoma in people with FH, and that included a control group of non-FH participants with either normal or symptomatic Achilles tendons, was considered eligible. All of the included studies were reviewed according to the STAndards for the Reporting of Diagnostic accuracy (STARD) method. A qualitative synthesis of the included studies was undertaken. RESULTS: Fifteen studies with 699 patients with FH and 868 non-FH participants were included. Among the non-FH participants, 26 individuals had other documented Achilles tendon pathology (trauma or overuse). Evaluation with the STARD checklist suggested that the quality of evidence was low. US imaging and MRI may have acceptable sensitivity in detecting tendon thickening associated with ATX. There is a wide range in the suggested thickness thresholds and in the estimates of diagnostic accuracy. CONCLUSIONS: A small amount of low-quality evidence suggests that ultrasonography or MRI can improve clinicians' accuracy in identifying ATX in people with FH, thereby identifying those with more severe coronary artery disease.