Browsing by Author "Huebner, Janet L"

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Open Access
A novel inflammatory biomarker, GlycA, associates with disease activity in rheumatoid arthritis and cardio-metabolic risk in BMI-matched controls.
(Arthritis Res Ther, 2016-04-12) Bartlett, David B; Connelly, Margery A; AbouAssi, Hiba; Bateman, Lori A; Tune, K Noelle; Huebner, Janet L; Kraus, Virginia B; Winegar, Deborah A; Otvos, James D; Kraus, William E; Huffman, Kim M
BACKGROUND: RA and CVD both have inflammation as part of the underlying biology. Our objective was to explore the relationships of GlycA, a measure of glycosylated acute phase proteins, with inflammation and cardiometabolic risk in RA, and explore whether these relationships were similar to those for persons without RA. METHODS: Plasma GlycA was determined for 50 individuals with mild-moderate RA disease activity and 39 controls matched for age, gender, and body mass index (BMI). Regression analyses were performed to assess relationships between GlycA and important markers of traditional inflammation and cardio-metabolic health: inflammatory cytokines, disease activity, measures of adiposity and insulin resistance. RESULTS: On average, RA activity was low (DAS-28 = 3.0 ± 1.4). Traditional inflammatory markers, ESR, hsCRP, IL-1β, IL-6, IL-18 and TNF-α were greater in RA versus controls (P < 0.05 for all). GlycA concentrations were significantly elevated in RA versus controls (P = 0.036). In RA, greater GlycA associated with disease activity (DAS-28; RDAS-28 = 0.5) and inflammation (RESR = 0.7, RhsCRP = 0.7, RIL-6 = 0.3: P < 0.05 for all); in BMI-matched controls, these inflammatory associations were absent or weaker (hsCRP), but GlycA was related to IL-18 (RhsCRP = 0.3, RIL-18 = 0.4: P < 0.05). In RA, greater GlycA associated with more total abdominal adiposity and less muscle density (Rabdominal-adiposity = 0.3, Rmuscle-density = -0.3, P < 0.05 for both). In BMI-matched controls, GlycA associated with more cardio-metabolic markers: BMI, waist circumference, adiposity measures and insulin resistance (R = 0.3-0.6, P < 0.05 for all). CONCLUSIONS: GlycA provides an integrated measure of inflammation with contributions from traditional inflammatory markers and cardio-metabolic sources, dominated by inflammatory markers in persons with RA and cardio-metabolic factors in those without.
Open Access
Age-Related Adverse Inflammatory and Metabolic Changes Begin Early in Adulthood.
(The journals of gerontology. Series A, Biological sciences and medical sciences, 2018-05-22) Parker, Daniel; Sloane, Richard; Pieper, Carl F; Hall, Katherine S; Kraus, Virginia B; Kraus, William E; Huebner, Janet L; Ilkayeva, Olga R; Bain, James R; Newby, L Kristin; Cohen, Harvey Jay; Morey, Miriam C
Aging is characterized by deleterious immune and metabolic changes, but the onset of these changes is unknown. We measured immune and metabolic biomarkers in adults beginning at age 30. To our knowledge, this is the first study to evaluate these biomarkers in adults aged 30 to over 80. Biomarkers were quantified in 961 adults. Tumor necrosis factor alpha (TNF-α), tumor necrosis factor receptor I (TNFR-I), tumor necrosis factor receptor II (TNFR-II), interleukin (IL)-2, IL-6, VCAM-I, D-Dimer, G-CSF, regulated on activation, normal T cell expressed and secreted (RANTES), matrix metalloproteinase-3 (MMP-3), adiponectin, and paraoxonase activity were measured by ELISA. Acylcarnitines and amino acids (AAs) were measured by mass spectrometry and reduced to a single factor using principal components analysis (PCA). Glycine was analyzed separately. The relationship between age and biomarkers was analyzed by linear regression with sex, race, and body mass index (BMI) as covariates. Age was positively correlated with TNF-α, TNFR-I, TNFR-II, IL-6, IL-2, VCAM-1, D-Dimer, MMP-3, adiponectin, acylcarnitines, and AAs. Age was negative correlated with G-CSF, RANTES, and paraoxonase activity. BMI was significant for all biomarkers except IL-2, VCAM-1, RANTES, paraoxonase activity, and the AA factor. Excluding MMP-3, greater BMI was associated with potentially adverse changes in biomarker concentrations. Age-related changes in immune and metabolic biomarkers, known to be associated with poor outcomes in older adults, begin as early as the thirties.
Open Access
Association of Biomarkers with Individual and Multiple Body Sites of Pain: The Johnston County Osteoarthritis Project.
(Journal of pain research, 2022-01) Norman, Katherine S; Goode, Adam P; Alvarez, Carolina; Hu, David; George, Steven Z; Schwartz, Todd A; Danyluk, Stephanie T; Fillipo, Rebecca; Kraus, Virginia B; Huebner, Janet L; Cleveland, Rebecca J; Jordan, Joanne M; Nelson, Amanda E; Golightly, Yvonne M
Introduction
Biochemical biomarkers may provide insight into musculoskeletal pain reported at individual or multiple body sites. The purpose of this study was to determine if biomarkers or pressure-pain threshold (PPT) were associated with individual or multiple sites of pain.
Methods
This cross-sectional analysis included 689 community-based participants. Self-reported symptoms (ie, pain, aching, or stiffness) were ascertained about the neck, upper back/thoracic, low back, shoulders, elbows, wrist, hands, hips, knees, ankles, and feet. Measured analytes included CXCL-6, RANTES, HA, IL-6, BDNF, OPG and NPY. A standard dolorimeter measured PPT. Logistic regression was used determine the association between biomarkers and PPT with individual and summed sites of pain.
Results
Increased IL-6 and HA were associated with knee pain (OR=1.30, 95% CI 1.03, 1.64) and (OR=1.32, 95% CI 1.01, 1.73) respectively; HA was also associated with elbow/wrist/hand pain (OR=1.60, 95% CI 1.22, 2.09). Those with increased NPY levels were less likely to have shoulder pain (OR=0.56, 95% CI 0.33, 0.93). Biomarkers HA (OR=1.50, 95% CI 1.07, 2.10), OPG (OR=1.74, 95% CI 1.00, 3.03), CXCL-6 (OR=1.75, 95% CI 1.02, 3.01) and decreased PPT (OR=3.97, 95% CI 2.22, 7.12) were associated with multiple compared to no sites of pain. Biomarker HA (OR=1.57, 95% CI 1.06, 2.32) and decreased PPT (OR=3.53, 95% CI 1.81, 6.88) were associated with multiple compared to a single site of pain.
Conclusion
Biomarkers of inflammation (HA, OPG, IL-6 and CXCL-6), pain (NPY) and PPT may help to understand the etiology of single and multiple pain sites.
Open Access
Cartilage mechanics in the guinea pig model of osteoarthritis studied with an osmotic loading method.
(Osteoarthritis and cartilage, 2004-05) Flahiff, Charlene M; Kraus, Virginia B; Huebner, Janet L; Setton, Lori A
To determine the material properties of articular cartilage in the Hartley guinea pig model of spontaneous osteoarthritis.Cartilage-bone samples from the medial femoral condyle and tibial plateau of 12 month-old guinea pig knees were subjected to osmotic loading. Site-matched swelling strains and fixed charge density values were used in a triphasic theoretical model for cartilage swelling to determine the modulus of the cartilage solid matrix. The degree of cartilage degeneration was assessed in adjacent tissue sections using a semi-quantitative histological grading scheme.Decreased values for both moduli and surface zone fixed charge density were associated with increasing grades of cartilage degeneration. Decreases in moduli reflect damage to the collagen matrix, which give rise to greater swelling strains.Histological evidence of cartilage degeneration was associated with impaired cartilage mechanics in the aging Hartley guinea pig.
Open Access
Changes in midbrain pain receptor expression, gait and behavioral sensitivity in a rat model of radiculopathy.
(Open Orthop J, 2012) Hwang, Priscilla Y; Allen, Kyle D; Shamji, Mohammed F; Jing, Liufang; Mata, Brian A; Gabr, Mostafa A; Huebner, Janet L; Kraus, Virginia B; Richardson, William J; Setton, Lori A
Intervertebral disc herniation may contribute to inflammatory processes that associate with radicular pain and motor deficits. Molecular changes at the affected dorsal root ganglion (DRG), spinal cord, and even midbrain, have been documented in rat models of radiculopathy or nerve injury. The objective of this study was to evaluate gait and the expression of key pain receptors in the midbrain in a rodent model of radiculopathy. Radiculopathy was induced by harvesting tail nucleus pulposus (NP) and placing upon the right L5 DRG in rats (NP-treated, n=12). Tail NP was discarded in sham-operated animals (n=12). Mechanical allodynia, weight-bearing, and gait were evaluated in all animals over time. At 1 and 4 weeks after surgery, astrocyte and microglial activation was tested in DRG sections. Midbrain sections were similarly evaluated for immunoreactivity to serotonin (5HT(2B)), mu-opioid (µ-OR), and metabotropic glutamate (mGluR4 and 5) receptor antibodies. NP-treated animals placed less weight on the affected limb 1 week after surgery and experienced mechanical hypersensitivity over the duration of the study. Astroctye activation was observed at DRGs only at 4 weeks after surgery. Findings for pain receptors in the midbrain of NP-treated rats included an increased expression of 5HT(2B) at 1, but not 4 weeks; increased expression of µ-OR and mGluR5 at 1 and 4 weeks (periaqueductal gray region only); and no changes in expression of mGluR4 at any point in this study. These observations provide support for the hypothesis that the midbrain responds to DRG injury with a transient change in receptors regulating pain responses.
Open Access
Chondroitin Sulfate Inhibits Monocyte Chemoattractant Protein-1 Release From 3T3-L1 Adipocytes: A New Treatment Opportunity for Obesity-Related Inflammation?
(Biomarker insights, 2017-01) Stabler, Thomas V; Montell, Eulàlia; Vergés, Josep; Huebner, Janet L; Kraus, Virginia Byers
Monocyte chemoattractant protein-1 (MCP-1) overproduction from inflamed adipose tissue is a major contributor to obesity-related metabolic syndromes. 3T3-L1 embryonic fibroblasts were cultured and differentiated into adipocytes using an established protocol. Adipocytes were treated with lipopolysaccharide (LPS) to induce inflammation and thus MCP-1 release. At the same time, varying concentrations of chondroitin sulfate (CS) were added in a physiologically relevant range (10-200 µg/mL) to determine its impact on MCP-1 release. Chondroitin sulfate, a natural glycosaminoglycan of connective tissue including the cartilage extracellular matrix, was chosen on the basis of our previous studies demonstrating its anti-inflammatory effect on macrophages. Because the main action of MCP-1 is to induce monocyte migration, cultured THP-1 monocytes were used to test whether CS at the highest physiologically relevant concentration could inhibit cell migration induced by human recombinant MCP-1. Chondroitin sulfate (100-200 µg/mL) inhibited MCP-1 release from inflamed adipocytes in a dose-dependent manner (P < .01, 95% confidence interval [CI]: -5.89 to -3.858 at 100 µg/mL and P < .001, 95% CI: -6.028 to -3.996 at 200 µg/mL) but had no effect on MCP-1-driven chemotaxis of THP-1 monocytes. In summary, CS could be expected to reduce macrophage infiltration into adipose tissue by reduction in adipocyte expression and release of MCP-1 and as such might reduce adipose tissue inflammation in response to pro-inflammatory stimuli such as LPS, now increasingly recognized to be relevant in vivo.
Open Access
CXCL10 is Upregulated in Synovium and Cartilage following Articular Fracture.
(J Orthop Res, 2017-09-14) Furman, Bridgette D; Kent, Collin L; Huebner, Janet L; Kraus, Virginia B; McNulty, Amy L; Guilak, Farshid; Olson, Steven A
The objective of this study was to investigate the expression of the chemokine CXCL10 and its role in joint tissues following articular fracture. We hypothesized that CXCL10 is upregulated following articular fracture and contributes to cartilage degradation associated with post-traumatic arthritis (PTA). To evaluate CXCL10 expression following articular fracture, gene expression was quantified in synovial tissue from knee joints of C57BL/6 mice that develop PTA following articular fracture, and MRL/MpJ mice that are protected from PTA. CXCL10 protein expression was assessed in human cartilage in normal, osteoarthritic (OA), and post-traumatic tissue using immunohistochemistry. The effects of exogenous CXCL10, alone and in combination with IL-1, on porcine cartilage explants were assessed by quantifying the release of catabolic mediators. Synovial tissue gene expression of CXCL10 was upregulated by joint trauma, peaking one day in C57BL/6 mice (25-fold) vs. three days post-fracture in MRL/MpJ mice (15-fold). CXCL10 protein in articular cartilage was most highly expressed following trauma compared with normal and OA tissue. In a dose dependent manner, exogenous CXCL10 significantly reduced total matrix metalloproteinase (MMP) and aggrecanase activity of culture media from cartilage explants. CXCL10 also trended toward a reduction in IL-1α-stimulated total MMP activity (p=0.09) and S-GAG (p=0.09), but not NO release. In conclusion, CXCL10 was upregulated in synovium and chondrocytes following trauma. However, exogenous CXCL10 did not induce a catabolic response in cartilage. CXCL10 may play a role in modulating the chondrocyte response to inflammatory stimuli associated with joint injury and the progression of PTA. This article is protected by copyright. All rights reserved.
Open Access
Cytokine biomarkers in tear film for primary open-angle glaucoma.
(Clin Ophthalmol, 2017) Gupta, Divakar; Wen, Joanne C; Huebner, Janet L; Stinnett, Sandra; Kraus, Virginia B; Tseng, Henry C; Walsh, Molly
PURPOSE: To determine the utility of tear film cytokines as biomarkers for early primary open-angle glaucoma (POAG). METHODS: Patients without POAG and eye drop-naïve patients with newly diagnosed POAG were recruited from an academic hospital-based glaucoma practice. Tear films of recruited patients were obtained and analyzed using a multiplex, high-sensitivity electrochemiluminescent enzyme-linked immunosorbent assay for proinflammatory cytokines (IFNγ, IL-10, IL-12p70, IL-13, IL-1β, IL-2, IL-4, IL-6, IL-8, and TNFα). RESULTS: Mean concentrations of tear film cytokines were lower in the glaucoma group for 8 of 10 cytokines tested. IL-12p70 (3.94±2.19 pg/mL in control vs 2.31±1.156 pg/mL in POAG;P=0.035) was significantly lower in the tear film of patients with newly diagnosed POAG. CONCLUSION: Proinflammatory cytokines were lower in eye drop-naïve newly diagnosed glaucoma patients. Tear film cytokine profiles may be used as biomarkers of early POAG.
Restricted
Diet-induced obesity differentially regulates behavioral, biomechanical, and molecular risk factors for osteoarthritis in mice.
(Arthritis Res Ther, 2010) Griffin, Timothy M; Fermor, Beverley; Huebner, Janet L; Kraus, Virginia B; Rodriguiz, Ramona M; Wetsel, William C; Cao, Li; Setton, Lori A; Guilak, Farshid
INTRODUCTION: Obesity is a major risk factor for the development of osteoarthritis in both weight-bearing and nonweight-bearing joints. The mechanisms by which obesity influences the structural or symptomatic features of osteoarthritis are not well understood, but may include systemic inflammation associated with increased adiposity. In this study, we examined biomechanical, neurobehavioral, inflammatory, and osteoarthritic changes in C57BL/6J mice fed a high-fat diet. METHODS: Female C57BL/6J mice were fed either a 10% kcal fat or a 45% kcal fat diet from 9 to 54 weeks of age. Longitudinal changes in musculoskeletal function and inflammation were compared with endpoint neurobehavioral and osteoarthritic disease states. Bivariate and multivariate analyses were conducted to determine independent associations with diet, percentage body fat, and knee osteoarthritis severity. We also examined healthy porcine cartilage explants treated with physiologic doses of leptin, alone or in combination with IL-1α and palmitic and oleic fatty acids, to determine the effects of leptin on cartilage extracellular matrix homeostasis. RESULTS: High susceptibility to dietary obesity was associated with increased osteoarthritic changes in the knee and impaired musculoskeletal force generation and motor function compared with controls. A high-fat diet also induced symptomatic characteristics of osteoarthritis, including hyperalgesia and anxiety-like behaviors. Controlling for the effects of diet and percentage body fat with a multivariate model revealed a significant association between knee osteoarthritis severity and serum levels of leptin, adiponectin, and IL-1α. Physiologic doses of leptin, in the presence or absence of IL-1α and fatty acids, did not substantially alter extracellular matrix homeostasis in healthy cartilage explants. CONCLUSIONS: These results indicate that diet-induced obesity increases the risk of symptomatic features of osteoarthritis through changes in musculoskeletal function and pain-related behaviors. Furthermore, the independent association of systemic adipokine levels with knee osteoarthritis severity supports a role for adipose-associated inflammation in the molecular pathogenesis of obesity-induced osteoarthritis. Physiologic levels of leptin do not alter extracellular matrix homeostasis in healthy cartilage, suggesting that leptin may be a secondary mediator of osteoarthritis pathogenesis.
Open Access
Effect of high-intensity interval training on muscle remodeling in rheumatoid arthritis compared to prediabetes.
(Arthritis research & therapy, 2018-12-27) Andonian, Brian J; Bartlett, David B; Huebner, Janet L; Willis, Leslie; Hoselton, Andrew; Kraus, Virginia B; Kraus, William E; Huffman, Kim M
BACKGROUND:Sarcopenic obesity, associated with greater risk of cardiovascular disease (CVD) and mortality in rheumatoid arthritis (RA), may be related to dysregulated muscle remodeling. To determine whether exercise training could improve remodeling, we measured changes in inter-relationships of plasma galectin-3, skeletal muscle cytokines, and muscle myostatin in patients with RA and prediabetes before and after a high-intensity interval training (HIIT) program. METHODS:Previously sedentary persons with either RA (n = 12) or prediabetes (n = 9) completed a 10-week supervised HIIT program. At baseline and after training, participants underwent body composition (Bod Pod®) and cardiopulmonary exercise testing, plasma collection, and vastus lateralis biopsies. Plasma galectin-3, muscle cytokines, muscle interleukin-1 beta (mIL-1β), mIL-6, mIL-8, muscle tumor necrosis factor-alpha (mTNF-α), mIL-10, and muscle myostatin were measured via enzyme-linked immunosorbent assays. An independent cohort of patients with RA (n = 47) and age-, gender-, and body mass index (BMI)-matched non-RA controls (n = 23) were used for additional analyses of galectin-3 inter-relationships. RESULTS:Exercise training did not reduce mean concentration of galectin-3, muscle cytokines, or muscle myostatin in persons with either RA or prediabetes. However, training-induced alterations varied among individuals and were associated with cardiorespiratory fitness and body composition changes. Improved cardiorespiratory fitness (increased absolute peak maximal oxygen consumption, or VO2) correlated with reductions in galectin-3 (r = -0.57, P = 0.05 in RA; r = -0.48, P = 0.23 in prediabetes). Training-induced improvements in body composition were related to reductions in muscle IL-6 and TNF-α (r < -0.60 and P <0.05 for all). However, the association between increased lean mass and decreased muscle IL-6 association was stronger in prediabetes compared with RA (Fisher r-to-z P = 0.0004); in prediabetes but not RA, lean mass increases occurred in conjunction with reductions in muscle myostatin (r = -0.92; P <0.05; Fisher r-to-z P = 0.026). Subjects who received TNF inhibitors (n = 4) or hydroxychloroquine (n = 4) did not improve body composition with exercise training. CONCLUSION:Exercise responses in muscle myostatin, cytokines, and body composition were significantly greater in prediabetes than in RA, consistent with impaired muscle remodeling in RA. To maximize physiologic improvements with exercise training in RA, a better understanding is needed of skeletal muscle and physiologic responses to exercise training and their modulation by RA disease-specific features or pharmacologic agents or both. TRIAL REGISTRATION:ClinicalTrials.gov Identifier: NCT02528344 . Registered on August 19, 2015.
Open Access
Field-Based Assessments of Behavioral Patterns During Shiftwork in Police Academy Trainees Using Wearable Technology.
(Journal of biological rhythms, 2022-06) Erickson, Melissa L; Wang, Will; Counts, Julie; Redman, Leanne M; Parker, Daniel; Huebner, Janet L; Dunn, Jessilyn; Kraus, William E
Circadian misalignment, as occurs in shiftwork, is associated with numerous negative health outcomes. Here, we sought to improve data labeling accuracy from wearable technology using a novel data pre-processing algorithm in 27 police trainees during shiftwork. Secondarily, we explored changes in four metabolic salivary biomarkers of circadian rhythm during shiftwork. Using a two-group observational study design, participants completed in-class training during dayshift for 6 weeks followed by either dayshift or nightshift field-training for 6 weeks. Using our novel algorithm, we imputed labels of circadian misaligned sleep episodes that occurred during daytime, which were previously were mislabeled as non-sleep by Garmin, supported by algorithm performance analysis. We next assessed changes to resting heart rate and sleep regularity index during dayshift versus nightshift field-training. We also examined changes in field-based assessments of salivary cortisol, uric acid, testosterone, and melatonin during dayshift versus nightshift. Compared to dayshift, nightshift workers experienced larger changes to resting heart rate, sleep regularity index (indicating reduced sleep regularity), and alterations in sleep/wake activity patterns accompanied by blunted salivary cortisol. Salivary uric acid and testosterone did not change. These findings show wearable technology combined with specialized data pre-processing can be used to monitor changes in behavioral patterns during shiftwork.
Open Access
In Vivo luminescent imaging of NF-κB activity and serum cytokine levels predict pain sensitivities in a rodent model of osteoarthritis.
(Arthritis Rheum, 2013-11-18) Bowles, Robby D; Mata, Brian A; Bell, Richard D; Mwangi, Timothy K; Huebner, Janet L; Kraus, Virginia B; Setton, Lori A
Objective: To investigate the relationship between NF-κB activity, cytokine levels, and pain sensitivities in a rodent model of osteoarthritis (OA). Method: OA was induced in transgenic NF-κB luciferase reporter mice via mono-iodoacetate (MIA) intra-articular injection. Using luminescent imaging we evaluated the temporal kinetics of NF-κB activity and its relationship to the development of pain sensitivities and serum cytokine levels in this model. Results: MIA induced a transient increase in joint-related NF-кB activity at early time points (day 3 post-injection) and an associated biphasic pain (mechanical allodynia) response. NF-кB activity, serum IL-6, IL-1β, and IL-10 accounted for ~75% of the variability in pain-related mechanical sensitivities in this model. Specifically, NF-кB activity was strongly correlated to mechanical allodynia and serum IL-6 levels in the inflammatory pain phase of this model (day 3), while serum IL-1β was strongly correlated to pain sensitivities in the chronic pain phase of the model (day 28). Conclusion: Our findings suggest that NF-кB activity, IL-6 and IL-1β may be playing distinct roles in pain sensitivity development in this model of arthritis and may act to distinguish the acute from chronic pain phases of this model. This work establishes luminescent imaging of NF-кB activity as a novel imaging biomarker of pain sensitivities in this model of OA. © 2013 American College of Rheumatology.
Open Access
Increase in Free and Total Plasma TGF-β1 Following Physical Activity.
(Cartilage, 2021-12) Han, Ashley J; Alexander, Louie C; Huebner, Janet L; Reed, Alexander B; Kraus, Virginia B
Objective
To evaluate effects of physical activity and food consumption on plasma concentrations of free and total transforming growth factor beta-1 (TGF-β1), beta-2 (TGF-β2), and beta-3 (TGF-β3) in individuals with knee osteoarthritis (OA).
Methods
Participants (n = 40 in 2 cohorts of 20; mean age 70 years) with radiographic knee OA were admitted overnight for serial blood sampling. Cohorts 1 and 2 assessed the impacts of food intake and activity, respectively, on TGF-β concentrations. Cohort 1 blood draws included 2 hours postprandial the evening of day 1 (T3), fasting before rising on day 2 (T0), nonfasting 1 hour after rising (T1B), and 4 hours after rising (T2). Cohort 2 blood draws included T3, T0, fasting 1 hour after rising and performing activities of daily living (T1A), and nonfasting 2 hours after rising (T1B). By sandwich ELISAs, we quantified plasma free and total TGF-β1 concentrations in all samples, and plasma total TGF-β2 and TGF-β3 in cohort 2.
Results
Free TGF-β1 represented a small fraction of the total systemic concentration (mean 0.026%). In cohort 2, free and total TGF-β1 and total TGF-β2 concentration significantly increased in fasting samples collected after an hour (T1A) of activities of daily living (free TGF-β1: P = 0.006; total TGF-β1: P < 0.001; total TGF-β2: P = 0.001). Total TGF-β3 increased nonsignificantly following activity (P = 0.590) and decreased (P = 0.035) after food consumption while resting (T1B).
Conclusions
Increased plasma concentrations of TGF-β with physical activity suggests activity should be standardized prior to TGF-β1 analyses.
Open Access
Initial displacement of the intra-articular surface after articular fracture correlates with PTA in C57BL/6 mice but not "superhealer" MRL/MpJ mice.
(Journal of orthopaedic research : official publication of the Orthopaedic Research Society, 2021-09) Vovos, Tyler J; Furman, Bridgette D; Huebner, Janet L; Kimmerling, Kelly A; Utturkar, Gangadhar M; Green, Cynthia L; Kraus, Virginia B; Guilak, Farshid; Olson, Steven A
Posttraumatic arthritis (PTA) occurs commonly after articular fracture and may arise, in part, from joint surface incongruity after injury. MRL/MpJ (MRL) "super-healer" mice are protected from PTA compared to C57BL/6 (B6) mice following articular fracture. However, the relationship between the initial displacement of the articular surface, biologic response, and susceptibility to PTA after fracture remains unclear. The objective of this study was to assess whether joint incongruity after articular fracture, as measured by in vivo micro-computed tomography (microCT), could predict pathomechanisms of PTA in mice. B6 and MRL mice (n = 12/strain) received a closed articular fracture (fx) of the left tibial plateau. Articular incongruity was quantified as bone surface deviations (BSD) for each in vivo microCT scan obtained from pre-fx to 8 weeks post-fx, followed by histologic assessment of arthritis. Serum concentrations of bone formation (PINP) and bone resorption (CTX-I) biomarkers were quantified longitudinally. Both strains showed increases in surface incongruity over time, as measured by increases in BSD. In B6 mice, acute surface incongruity was significantly correlated to the severity of PTA (R ² = 0.988; p = .0006), but not in MRL mice (R ² = 0.224; p = .220). PINP concentrations significantly decreased immediately post-fx in B6 mice (p = .023) but not in MRL mice, indicating higher bone synthesis in MRL mice. MRL/MpJ mice demonstrate a unique biologic response to articular fracture such that the observed articular bone surface displacement does not correlate with the severity of subsequent PTA. Clinical Relevance: Identifying therapies to enhance acute biologic repair following articular fracture may mitigate the risk of articular surface displacement for PTA.
Open Access
Kinematic and dynamic gait compensations resulting from knee instability in a rat model of osteoarthritis.
(Arthritis Res Ther, 2012-04-17) Allen, Kyle D; Mata, Brian A; Gabr, Mostafa A; Huebner, Janet L; Adams, Samuel B; Kraus, Virginia B; Schmitt, Daniel O; Setton, Lori A
INTRODUCTION: Osteoarthritis (OA) results in pain and disability; however, preclinical OA models often focus on joint-level changes. Gait analysis is one method used to evaluate both preclinical OA models and OA patients. The objective of this study is to describe spatiotemporal and ground reaction force changes in a rat medial meniscus transection (MMT) model of knee OA and to compare these gait measures with assays of weight bearing and tactile allodynia. METHODS: Sixteen rats were used in the study. The medial collateral ligament (MCL) was transected in twelve Lewis rats (male, 200 to 250 g); in six rats, the medial meniscus was transected, and the remaining six rats served as sham controls. The remaining four rats served as naïve controls. Gait, weight-bearing as measured by an incapacitance meter, and tactile allodynia were assessed on postoperative days 9 to 24. On day 28, knee joints were collected for histology. Cytokine concentrations in the serum were assessed with a 10-plex cytokine panel. RESULTS: Weight bearing was not affected by sham or MMT surgery; however, the MMT group had decreased mechanical paw-withdrawal thresholds in the operated limb relative to the contralateral limb (P = 0.017). The gait of the MMT group became increasingly asymmetric from postoperative days 9 to 24 (P = 0.020); moreover, MMT animals tended to spend more time on their contralateral limb than their operated limb while walking (P < 0.1). Ground reaction forces confirmed temporal shifts in symmetry and stance time, as the MMT group had lower vertical and propulsive ground reaction forces in their operated limb relative to the contralateral limb, naïve, and sham controls (P < 0.05). Levels of interleukin 6 in the MMT group tended to be higher than naïve controls (P = 0.072). Histology confirmed increased cartilage damage in the MMT group, consistent with OA initiation. Post hoc analysis revealed that gait symmetry, stance time imbalance, peak propulsive force, and serum interleukin 6 concentrations had significant correlations to the severity of cartilage lesion formation. CONCLUSION: These data indicate significant gait compensations were present in the MMT group relative to medial collateral ligament (MCL) injury (sham) alone and naïve controls. Moreover, these data suggest that gait compensations are likely driven by meniscal instability and/or cartilage damage, and not by MCL injury alone.
Open Access
Molecular alterations in skeletal muscle in rheumatoid arthritis are related to disease activity, physical inactivity, and disability.
(Arthritis Res Ther, 2017-01-23) Huffman, Kim M; Jessee, Ryan; Andonian, Brian; Davis, Brittany N; Narowski, Rachel; Huebner, Janet L; Kraus, Virginia B; McCracken, Julie; Gilmore, Brian F; Tune, K Noelle; Campbell, Milton; Koves, Timothy R; Muoio, Deborah M; Hubal, Monica J; Kraus, William E
BACKGROUND: To identify molecular alterations in skeletal muscle in rheumatoid arthritis (RA) that may contribute to ongoing disability in RA. METHODS: Persons with seropositive or erosive RA (n = 51) and control subjects matched for age, gender, race, body mass index (BMI), and physical activity (n = 51) underwent assessment of disease activity, disability, pain, physical activity and thigh muscle biopsies. Muscle tissue was used for measurement of pro-inflammatory markers, transcriptomics, and comprehensive profiling of metabolic intermediates. Groups were compared using mixed models. Bivariate associations were assessed with Spearman correlation. RESULTS: Compared to controls, patients with RA had 75% greater muscle concentrations of IL-6 protein (p = 0.006). In patients with RA, muscle concentrations of inflammatory markers were positively associated (p < 0.05 for all) with disease activity (IL-1β, IL-8), disability (IL-1β, IL-6), pain (IL-1β, TNF-α, toll-like receptor (TLR)-4), and physical inactivity (IL-1β, IL-6). Muscle cytokines were not related to corresponding systemic cytokines. Prominent among the gene sets differentially expressed in muscles in RA versus controls were those involved in skeletal muscle repair processes and glycolytic metabolism. Metabolic profiling revealed 46% higher concentrations of pyruvate in muscle in RA (p < 0.05), and strong positive correlation between levels of amino acids involved in fibrosis (arginine, ornithine, proline, and glycine) and disability (p < 0.05). CONCLUSION: RA is accompanied by broad-ranging molecular alterations in skeletal muscle. Analysis of inflammatory markers, gene expression, and metabolic intermediates linked disease-related disruptions in muscle inflammatory signaling, remodeling, and metabolic programming to physical inactivity and disability. Thus, skeletal muscle dysfunction might contribute to a viscous cycle of RA disease activity, physical inactivity, and disability.
Open Access
Relationships amongst osteoarthritis biomarkers, dynamic knee joint load, and exercise: results from a randomized controlled pilot study.
(BMC Musculoskelet Disord, 2013-03-27) Hunt, Michael A; Pollock, Courtney L; Kraus, Virginia Byers; Saxne, Tore; Peters, Sue; Peters, Sue; Huebner, Janet L; Sayre, Eric C; Cibere, Jolanda
BACKGROUND: Little is known about the relationships of circulating levels of biomarkers of cartilage degradation with biomechanical outcomes relevant to knee osteoarthritis (OA) or biomarker changes following non-pharmacological interventions. The objectives of this exploratory, pilot study were to: 1) examine relationships between biomarkers of articular cartilage degradation and synthesis with measures of knee joint load during walking, and 2) examine changes in these biomarkers following 10 weeks of strengthening exercises. METHODS: Seventeen (8 male, 9 female; 66.1 +/- 11.3 years of age) individuals with radiographically-confirmed medial tibiofemoral OA participated. All participants underwent a baseline testing session where serum and urine samples were collected, followed by a three-dimensional motion analysis. Motion analysis was used to calculate the external knee adduction moment (KAM) peak value and impulse. Following baseline testing, participants were randomized to either 10 weeks of: 1) physiotherapist-supervised lower limb muscle strengthening exercises, or 2) no exercises (control). Identical follow-up testing was conducted 11 weeks after baseline. Biomarkers included: urinary C-telopeptide of type II collagen (uCTX-II) and type II collagen cleavage neoepitope (uC2C), serum cartilage oligomeric matrix protein (sCOMP), serum hyaluronic acid (sHA) and serum C-propeptide of type II procollagen (sCPII). Linear regression analysis was used to examine relationships between measures of the KAM and biomarker concentrations as baseline, as well as between-group differences following the intervention. RESULTS: KAM impulse predicted significant variation in uCTX-II levels at baseline (p = 0.04), though not when controlling for disease severity and walking speed (p = 0.33). KAM impulse explained significant variation in the ratio uCTX-II;sCPII even when controlling for additional variables (p = 0.04). Following the intervention, changes in sCOMP were significantly greater in the exercise group compared to controls (p = 0.04). On average those in the control group experienced a slight increase in sCOMP and uCTX-II, while those in the exercise group experienced a reduction. No other significant findings were observed. CONCLUSIONS: This research provides initial evidence of a potential relationship between uCTX-II and knee joint load measures in patients with medial tibiofemoral knee OA. However, this relationship became non-significant after controlling for disease severity and walking speed, suggesting further research is necessary. It also appears that sCOMP is amenable to change following a strengthening intervention, suggesting a potential beneficial role of exercise on cartilage structure. TRIAL REGISTRATION: Clinicaltrials.gov NCT01241812.
Open Access
Select Biomarkers on the Day of Anterior Cruciate Ligament Reconstruction Predict Poor Patient-Reported Outcomes at 2-Year Follow-Up: A Pilot Study.
(BioMed research international, 2018-01) Lattermann, Christian; Conley, Caitlin E-W; Johnson, Darren L; Reinke, Emily K; Huston, Laura J; Huebner, Janet L; Chou, Ching-Heng; Kraus, Virginia B; Spindler, Kurt P; Jacobs, Cale A
Background:The majority of patients develop posttraumatic osteoarthritis within 15 years of anterior cruciate ligament (ACL) injury. Inflammatory and chondrodegenerative biomarkers have been associated with both pain and the progression of osteoarthritis; however, it remains unclear if preoperative biomarkers differ for patients with inferior postoperative outcomes. Hypothesis/Purpose:The purpose of this pilot study was to compare biomarkers collected on the day of ACL reconstruction between patients with "good" or "poor" 2-year postoperative outcomes. We hypothesized that inflammatory cytokines and chondrodegenerative biomarker concentrations would be significantly greater in patients with poorer outcomes. Study Design:Prospective cohort design. Methods:22 patients (9 females, 13 males; age = 19.5 ± 4.1 years; BMI = 24.1 ± 3.6 kg/m2) previously enrolled in a randomized trial evaluating early anti-inflammatory treatment after ACL injury. Biomarkers of chondrodegeneration and inflammation were assessed from synovial fluid (sf) samples collected on the day of ACL reconstruction. Participants completed Knee Injury and Osteoarthritis Outcome Score (KOOS) and International Knee Documentation Committee (IKDC) questionnaires two years following surgery. Patients were then categorized based on whether their KOOS Quality of Life (QOL) score surpassed the Patient Acceptable Symptom State (PASS) threshold of 62.5 points or the IKDC PASS threshold of 75.9 points. Results:Patients that failed to reach the QOL PASS threshold after surgery (n = 6, 27%) had significantly greater sf interleukin-1 alpha (IL-1α; p = 0.004), IL-1 receptor antagonist (IL-1ra; p = 0.03), and matrix metalloproteinase-9 (MMP-9; p = 0.01) concentrations on the day of surgery. Patients that failed to reach the IKDC PASS threshold (n = 9, 41%) had significantly greater sf IL-1α (p = 0.02). Conclusion:These pilot data suggest that initial biochemical changes after injury may be an indicator of poor outcomes that are not mitigated by surgical stabilization alone. Biological adjuvant treatment in addition to ACL reconstruction may be beneficial; however, these data should be used for hypothesis generation and more definitive randomized clinical trials are necessary.
Open Access
Targeting pro-inflammatory cytokines following joint injury: acute intra-articular inhibition of interleukin-1 following knee injury prevents post-traumatic arthritis.
(Arthritis Res Ther, 2014-06-25) Furman, Bridgette D; Mangiapani, Daniel S; Zeitler, Evan; Bailey, Karsyn N; Horne, Phillip H; Huebner, Janet L; Kraus, Virginia B; Guilak, Farshid; Olson, Steven A
INTRODUCTION: Post-traumatic arthritis (PTA) is a progressive, degenerative response to joint injury, such as articular fracture. The pro-inflammatory cytokines, interleukin 1(IL-1) and tumor necrosis factor alpha (TNF-α), are acutely elevated following joint injury and remain elevated for prolonged periods post-injury. To investigate the role of local and systemic inflammation in the development of post-traumatic arthritis, we targeted both the initial acute local inflammatory response and a prolonged 4 week systemic inflammatory response by inhibiting IL-1 or TNF-α following articular fracture in the mouse knee. METHODS: Anti-cytokine agents, IL-1 receptor antagonist (IL-1Ra) or soluble TNF receptor II (sTNFRII), were administered either locally via an acute intra-articular injection or systemically for a prolonged 4 week period following articular fracture of the knee in C57BL/6 mice. The severity of arthritis was then assessed at 8 weeks post-injury in joint tissues via histology and micro computed tomography, and systemic and local biomarkers were assessed in serum and synovial fluid. RESULTS: Intra-articular inhibition of IL-1 significantly reduced cartilage degeneration, synovial inflammation, and did not alter bone morphology following articular fracture. However, systemic inhibition of IL-1, and local or systemic inhibition of TNF provided no benefit or conversely led to increased arthritic changes in the joint tissues. CONCLUSION: These results show that intra-articular IL-1, rather than TNF-α, plays a critical role in the acute inflammatory phase of joint injury and can be inhibited locally to reduce post-traumatic arthritis following a closed articular fracture. Targeted local inhibition of IL-1 following joint injury may represent a novel treatment option for PTA.
Open Access
Ten weeks of high-intensity interval walk training is associated with reduced disease activity and improved innate immune function in older adults with rheumatoid arthritis: a pilot study.
(Arthritis research & therapy, 2018-06-14) Bartlett, David B; Willis, Leslie H; Slentz, Cris A; Hoselton, Andrew; Kelly, Leslie; Huebner, Janet L; Kraus, Virginia B; Moss, Jennifer; Muehlbauer, Michael J; Spielmann, Guillaume; Kraus, William E; Lord, Janet M; Huffman, Kim M
BACKGROUND:Rheumatoid arthritis (RA) is a chronic inflammatory disease in which adults have significant joint issues leading to poor health. Poor health is compounded by many factors, including exercise avoidance and increased risk of opportunistic infection. Exercise training can improve the health of patients with RA and potentially improve immune function; however, information on the effects of high-intensity interval training (HIIT) in RA is limited. We sought to determine whether 10 weeks of a walking-based HIIT program would be associated with health improvements as measured by disease activity and aerobic fitness. Further, we assessed whether HIIT was associated with improved immune function, specifically antimicrobial/bacterial functions of neutrophils and monocytes. METHODS:Twelve physically inactive adults aged 64 ± 7 years with either seropositive or radiographically proven (bone erosions) RA completed 10 weeks of high-intensity interval walking. Training consisted of 3 × 30-minute sessions/week of ten ≥ 60-second intervals of high intensity (80-90% VO2reserve) separated by similar bouts of lower-intensity intervals (50-60% VO2reserve). Pre- and postintervention assessments included aerobic and physical function; disease activity as measured by Disease Activity score in 28 joints (DAS28), self-perceived health, C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR); plasma interleukin (IL)-1β, IL-6, chemokine (C-X-C motif) ligand (CXCL)-8, IL-10, and tumor necrosis factor (TNF)-α concentrations; and neutrophil and monocyte phenotypes and functions. RESULTS:Despite minimal body composition change, cardiorespiratory fitness increased by 9% (change in both relative and absolute aerobic capacity; p < 0.001), and resting blood pressure and heart rate were both reduced (both p < 0.05). Postintervention disease activity was reduced by 38% (DAS28; p = 0.001) with significant reductions in ESR and swollen joints as well as improved self-perceived health. Neutrophil migration toward CXCL-8 (p = 0.003), phagocytosis of Escherichia coli (p = 0.03), and ROS production (p < 0.001) all increased following training. The frequency of cluster of differentiation 14-positive (CD14+)/CD16+ monocytes was reduced (p = 0.002), with both nonclassical (CD14dim/CD16bright) and intermediate (CD14bright/CD16positive) monocytes being reduced (both p < 0.05). Following training, the cell surface expression of intermediate monocyte Toll-like receptor 2 (TLR2), TLR4, and HLA-DR was reduced (all p < 0.05), and monocyte phagocytosis of E. coli increased (p = 0.02). No changes were observed for inflammatory markers IL-1β, IL-6, CXCL-8, IL-10, CRP, or TNF-α. CONCLUSIONS:We report for the first time, to our knowledge, that a high-intensity interval walking protocol in older adults with stable RA is associated with reduced disease activity, improved cardiovascular fitness, and improved innate immune functions, indicative of reduced infection risk and inflammatory potential. Importantly, the exercise program was well tolerated by these patients. TRIAL REGISTRATION:ClinicalTrials.gov, NCT02528344 . Registered on 19 August 2015.

Browsing by Author "Huebner, Janet L"

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