Elevated proinflammatory cytokines in response to mechanical stimulus are associated with reduced knee loading 2 years after anterior cruciate ligament reconstruction.

BACKGROUND: The aim of this study was to test the hypothesis that proinflammatory cytokines correlate with knee loading mechanics during gait following a mechanical walking stimulus in subjects 2 years after anterior cruciate ligament reconstruction. Elevated systemic levels of proinflammatory cytokines can be sustained for years after injury. Considering roughly 50% of these patients progress to Osteoarthritis 10-15 years after injury, a better understanding of the role of proinflammatory cytokines such as tumor necrosis factor-α and Interleukin-1ß on Osteoarthritis risk is needed. METHODS: Serum proinflammatory cytokines concentrations were measured in 21 subjects 2 years after unilateral ACLR from blood drawn at rest and 3.5 h after 30 min of walking. An optoelectronic system and a force plate measured subjects' knee kinetics. Correlations were tested between inflammatory marker response and knee extension and knee adduction moments. FINDINGS: Changes in proinflammatory cytokines due to mechanical stimulus were correlated (R = 0.86) and showed substantial variation between subjects in both cytokines at 3.5 h post-walk. Knee loading correlated with 3.5-h changes in tumor necrosis factor-α concentration (Knee extension moment: R = -0.5, Knee adduction moment: R = -0.5) and Interleukin-1ß concentration (Knee extension moment: R = -0.44). However, no significant changes in concentrations were observed in tumor necrosis factor-α and Interleukin-1ß when comparing baseline and post walking stimulus conditions. INTERPRETATION: The significant associations between changes in serum proinflammatory markers following a mechanical stimulus and gait metrics in subjects at risk for developing Osteoarthritis underscore the importance of investigating the interaction between biomarkers and biomechanical factors in Osteoarthritis development.

Cartilage oligomeric matrix protein responses to a mechanical stimulus associate with ambulatory loading in individuals with anterior cruciate ligament reconstruction.

Mechanical factors have been implicated in the development of osteoarthritis after anterior cruciate ligament (ACL) reconstruction. This study tested for associations between ambulatory joint loading (total joint moment [TJM] and vertical ground reaction force [vGRF]) and changes in serum levels of cartilage oligomeric matrix protein (COMP) in response to a mechanical stimulus (30-min walk) in individuals with ACL reconstruction. Twenty-five subjects (mean age: 34.5 ± 9.8 years; 2.2 ± 0.2 years post-surgery) with primary unilateral ACL reconstruction underwent gait analysis for assessment of peak vGRF and TJM first (TJM1) and second (TJM2) peaks. Serum COMP concentrations were measured by enzyme-linked immunosorbent assay immediately before, 3.5 h, and 5.5 h after a 30-min walk. Pearson correlation coefficients and backward stepwise multiple linear regression analysis, with adjustments for age, sex, body mass index, and between-limb speed difference, assessed associations between changes in COMP and between-limb differences in joint loading parameters. Greater TJM1 (R = 0.542, p = 0.005), TJM2 (R = 0.460, p = 0.021), and vGRF (R = 0.577, p = 0.003) in the ACL-reconstructed limb as compared to the contralateral limb were associated with higher COMP values 3.5 h following the 30-min walk. Change in COMP at 5.5 h became a significant predictor of the between-limb difference in TJM1 and vGRF in multivariate analyses after accounting for the between-limb speed difference. These results demonstrate that higher TJM and vGRF in the ACLR limb as compared to the contralateral limb are associated with higher relative COMP levels 3.5 and 5.5 h after a 30-min walk. Future work should investigate the effect of therapies to alter joint loading on the biological response in individuals after ACL reconstruction.

Visualizing pre-osteoarthritis: Integrating MRI UTE-T2* with mechanics and biology to combat osteoarthritis-The 2019 Elizabeth Winston Lanier Kappa Delta Award.

Osteoarthritis (OA) is a leading cause of pain and disability for which disease-modifying treatments remain lacking. This is because the symptoms and radiographic changes of OA occur after the onset of likely irreversible changes. Defining and treating earlier disease states are therefore needed to delay or to halt OA progression. Taking this concept a step further, studying OA pathogenesis before disease onset by characterizing potentially reversible markers of increased OA risk to identify a state of "pre-osteoarthritis (pre-OA)" shifts the paradigm towards OA prevention. The purpose of this review is to summarize the 42 studies comprising the 2019 Kappa Delta Elizabeth Lanier Award where conceptualization of a systems-based definition for "pre-osteoarthritis (pre-OA)" was followed by demonstration of potentially reversible markers of heightened OA risk in patients after anterior cruciate ligament (ACL) injury and reconstruction. In the process, these efforts contributed a new magnetic resonance imaging method of ultrashort echo time (UTE) enhanced T2* mapping to visualize joint tissue damage before the development of irreversible changes. The studies presented here support a transformative approach to OA that accounts for interactions between mechanical, biological, and structural markers of OA risk to develop and evaluate new treatment strategies that can delay or prevent the onset of clinical disease. This body of work was inspired by and performed for patients. Shifting the paradigm from attempting to modify symptomatic radiographic OA towards monitoring and reversing markers of "pre-OA" opens the door for transforming the clinical approach to OA from palliation to prevention.

Patient-Reported Outcomes and Knee Mechanics Correlate With Patellofemoral Deep Cartilage UTE-T2* 2 Years After Anterior Cruciate Ligament Reconstruction.

BACKGROUND: Patellofemoral joint degeneration and dysfunction after anterior cruciate ligament reconstruction (ACLR) are increasingly recognized as contributors to poor clinical outcomes. PURPOSE: To determine if greater deep cartilage matrix disruption at 2 years after ACLR, as assessed by elevated patellofemoral magnetic resonance imaging (MRI) ultrashort echo time-enhanced T2* (UTE-T2*), is correlated with (1) worse patient-reported knee function and pain and (2) gait metrics related to patellofemoral tracking and loading, such as greater external rotation of the tibia at heel strike, reduced knee flexion moment (as a surrogate of quadriceps function), and greater knee flexion angle at heel strike. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: MRI UTE-T2* relaxation times in patellar and trochlear deep cartilage were compared with patient-reported outcomes and ambulatory gait metrics in 60 patients with ACLR at 2 years after reconstruction. ACLR gait metrics were compared with those of 60 uninjured reference patients matched by age, body mass index, and sex. ACLR UTE-T2* values were compared with those of 20 uninjured reference patients. RESULTS: Higher trochlear UTE-T2* values were associated with worse Knee injury and Osteoarthritis Outcome Scores (KOOS) Sport/Recreation subscale scores (rho = -0.32; P = .015), and showed a trend for association with worse KOOS Pain subscale scores (rho = -0.26; P = .045). At 2 years after ACLR, greater external rotation of the tibia at heel strike was associated with higher patellar UTE-T2* values (R = 0.40; P = .002); greater knee flexion angle at heel strike was associated with higher trochlear UTE-T2* values (rho = 0.39; P = .002); and greater knee flexion moment showed a trend for association with higher trochlear UTE-T2* values (rho = 0.30; P = .019). Patellar cartilage UTE-T2* values, knee flexion angle at heel strike, and external rotation of the tibia at heel strike were all elevated in ACLR knees as compared with reference knees (P = .029, .001, and .044, respectively). CONCLUSION: Patellofemoral deep cartilage matrix disruption, as assessed by MRI UTE-T2*, was associated with reduced sports and recreational function and with gait metrics reflective of altered patellofemoral loading. As such, the findings provide new mechanistic information important to improving clinical outcomes related to patellofemoral dysfunction after ACLR.

MRI UTE-T2* shows high incidence of cartilage subsurface matrix changes 2 years after ACL reconstruction.

Alteration of deep cartilage matrix has been observed following anterior cruciate ligament (ACL) injury, evidenced by elevated MRI UTE-T2* values measured in small, 2-D cartilage regions of interest. This Level I diagnostic study seeks to more thoroughly evaluate deep cartilage matrix changes to medial tibiofemoral UTE-T2* maps 2 years after ACL reconstruction and examine the relative utilities of 3-D compared to 2-D assessments of cartilage UTE-T2* maps. Thirty-eight ACL-reconstructed and 20 uninjured subjects underwent MRI UTE-T2* mapping. "Small" single mid-sagittal 2-D and larger 3-D "tread mark" regions of interest were manually segmented and found to be correlated in medial cartilage (r > 0.58, p < 0.005). 3-D analyses of UTE-T2* maps showed differences to medial tibial cartilage between ACL-reconstructed and uninjured subjects (p = 0.007) that were not detected by smaller 2-D regions (p > 0.46). Quantitative comparisons show 14/38 (37%) ACL-reconstructed subjects have values >2 standard deviations higher than uninjured controls. Among a subset of ACL-reconstructed subjects with no morphologic MRI evidence of medial tibiofemoral cartilage or meniscal pathology (n = 12), elevated UTE-T2* values in "small" 2-D femoral (p = 0.011), but not larger 3-D tread mark regions of interest (p > 0.13), were observed. These data show the utility of 2-D UTE-T2* assessments of mid-sagittal weight-bearing regions of medial femoral cartilage for identifying subclinical deep cartilage matrix changes 2 years after ACLR. Clinical Significance: Mid-sagittal single slice 2-D UTE-T2* mapping may be an efficient means to assess medial femoral cartilage for subsurface matrix changes early after ACL reconstruction while 3-D assessments provide additional sensitivity to changes in the medial tibial plateau. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:370-377, 2019.

Cartilage Subsurface Changes to Magnetic Resonance Imaging UTE-T2* 2 Years After Anterior Cruciate Ligament Reconstruction Correlate With Walking Mechanics Associated With Knee Osteoarthritis.

BACKGROUND: Anterior cruciate ligament (ACL) injury increases risk for posttraumatic knee osteoarthritis (OA). Quantitative ultrashort echo time enhanced T2* (UTE-T2*) mapping shows promise for early detection of potentially reversible subsurface cartilage abnormalities after ACL reconstruction (ACLR) but needs further validation against established clinical metrics of OA risk such as knee adduction moment (KAM) and mechanical alignment. HYPOTHESIS: Elevated UTE-T2* values in medial knee cartilage 2 years after ACLR correlate with varus alignment and higher KAM during walking. STUDY DESIGN: Cohort study (diagnosis); Level of evidence, 2. METHODS: Twenty patients (mean age, 33.1 ± 10.5 years; 11 female) 2 years after ACLR underwent 3.0-T knee magnetic resonance imaging (MRI), radiography, and gait analysis, after which mechanical alignment was measured, KAM during walking was calculated, and UTE-T2* maps were generated. The mechanical axis and the first and second peaks of KAM (KAM1 and KAM2, respectively) were tested using linear regressions for correlations with deep UTE-T2* values in the central and posterior medial femoral condyle (cMFC and pMFC, respectively) and central medial tibial plateau (cMTP). UTE-T2* values from ACL-reconstructed patients were additionally compared with those of 14 uninjured participants (mean age, 30.9 ± 8.9 years; 6 female) using Mann-Whitney U and standard t tests. RESULTS: Central weightbearing medial compartment cartilage of ACL-reconstructed knees was intact on morphological MRI. Mean UTE-T2* values were elevated in both the cMFC and pMFC of ACL-reconstructed knees compared with those of uninjured knees ( P = .003 and P = .012, respectively). In ACL-reconstructed knees, UTE-T2* values of cMFC cartilage positively correlated with increasing varus alignment ( R = 0.568). Higher UTE-T2* values in cMFC and cMTP cartilage of ACL-reconstructed knees also correlated with greater KAM1 ( R = 0.452 and R = 0.463, respectively) and KAM2 ( R = 0.465 and R = 0.764, respectively) and with KAM2 in pMFC cartilage ( R = 0.602). CONCLUSION: Elevated deep UTE-T2* values of medial knee cartilage 2 years after ACLR correlate with 2 clinical markers of increased risk of medial knee OA. These results support the clinical utility of MRI UTE-T2* for early diagnosis of subsurface cartilage abnormalities. Longitudinal follow-up of larger cohorts is needed to determine the predictive and staging potential of UTE-T2* for posttraumatic OA.

Mechanically stimulated biomarkers signal cartilage changes over 5 years consistent with disease progression in medial knee osteoarthritis patients.

Using serum biomarkers to assess osteoarthritis (OA) disease state and risks of progression remain challenging. This study tested the hypothesis that changes to serum biomarkers in response to a mechanical stimulus in patients with medial knee OA signal cartilage thickness changes 5 years later. Specifically, serum concentrations of a collagen degradation marker (C1,2C) and a chondroitin sulfate synthesis marker (CS846) were measured 0.5 and 5.5 hours after a 30-min walk in 16 patients. Regional cartilage thickness changes measured from magnetic resonance images obtained at study entry and at 5-year follow-up were tested for correlations with baseline biomarker changes after mechanical stimulus, and for differences between groups stratified based on whether biomarker levels increased or decreased. Results showed that an increase in the degradation biomarker C1,2C correlated with cartilage thinning of the lateral tibia (R = -0.63, p = 0.009), whereas an increase in the synthesis marker CS846 correlated with cartilage thickening of the lateral femur (R = 0.76, p = 0.001). Changes in C1,2C and CS846 were correlated (R2 = 0.28, p = 0.037). Subjects with increased C1,2C had greater (p = 0.05) medial tibial cartilage thinning than those with decreased C1,2C. In conclusion, the mechanical stimulus appeared to metabolically link the biomarker responses where biomarker increases signaled more active OA disease states. The findings of medial cartilage thinning for patients with increases in the degradation marker and correlation of cartilage thickening in the less involved lateral femur with increases in the synthetic marker were consistent with progression of medial compartment OA. Thus, the mechanical stimulus facilitated assessing OA disease states using serum biomarkers. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:891-897, 2018.

Early Changes in Knee Center of Rotation During Walking After Anterior Cruciate Ligament Reconstruction Correlate With Later Changes in Patient-Reported Outcomes.

BACKGROUND: Altered knee kinematics after anterior cruciate ligament injury and reconstruction (ACLR) have been implicated in the development of posttraumatic osteoarthritis (PTOA), leading to poor long-term clinical outcomes. PURPOSE: This study was conducted to determine (1) whether the average knee center of rotation (KCOR), a multidimensional metric of knee kinematics, of the ACL-reconstructed knee during walking differs from that of the uninjured contralateral knee; (2) whether KCOR changes between 2 and 4 years after surgery; and (3) whether early KCOR changes predict patient-reported outcomes 8 years after ACLR. STUDY DESIGN: Descriptive laboratory study. METHODS: Twenty-six human participants underwent gait analysis with calculation of bilateral KCOR during walking at 2 and 4 years after unilateral ACLR. Knee injury and Osteoarthritis Outcome Score (KOOS) and Lysholm score results were collected at 2, 4, and 8 years after ACLR in 13 of these participants. RESULTS: The ACL-reconstructed knee showed greater medial compartment motion because of pivoting about a more lateral KCOR ( P = .03) than the contralateral knee at 2 years. KCOR became less lateral over time ( P = .047), with values approaching those of the uninjured knee by 4 years ( P = .55). KCOR was also more anterior in the ACL-reconstructed knee at 2 years ( P = .02). Between 2 and 4 years, KCOR moved posteriorly in 16 (62%) and anteriorly in 10 (38%) participants. Increasing the anterior position of KCOR in the ACL-reconstructed knee from 2 to 4 years correlated with worsening clinical outcomes at 4 years (KOOS-Quality of Life, R2 = 0.172) and more strongly at 8 years (Lysholm score, R2 = 0.41; KOOS-Pain, R2 = 0.37; KOOS-Symptoms, R2 = 0.58; and KOOS-Quality of Life, R2 = 0.50). CONCLUSION: The observed changes to KCOR during walking between 2 and 4 years after ACLR show progressive improvement toward kinematic symmetry over the 2-year follow-up. The correlation between increasingly abnormal kinematics and worsening clinical outcomes years later in a subset of participants provides a potential explanation for the incidence of PTOA after ACLR.

Effects of high heel wear and increased weight on the knee during walking.

Knee osteoarthritis (OA), a leading cause of disability, is more prevalent in women than men. Wearing high heeled shoes has been implicated as a potential contributing factor for the higher lifetime risk of osteoarthritis in women. This study tests the hypotheses that changes to knee kinematics and kinetics observed during high heeled walking increase in magnitude with increasing heel height and are accentuated by a 20% increase in weight. Fourteen healthy females were tested using marker-based gait analysis in combinations of footwear (flat athletic shoe, 3.8 cm and 8.3 cm heeled shoes) and weight (with and without 20% bodyweight vest). At preferred walking speed, knee flexion angle at heel-strike and midstance increased with increasing heel height and weight. Maximum knee extension moment during loading response decreased with added weight; maximum knee extension moment during terminal stance decreased with heel height; maximum adduction moments increased with heel height. Many of the changes observed with increasing heel height and weight were similar to those seen with aging and OA progression. This suggests that high heel use, especially in combination with additional weight, may contribute to increased OA risk in women.