Cartilage Biomarkers Research Articles

Equine-assisted service’s effect on cartilage and skeletal biomarkers for adults and older adults with arthritis: A pilot study

ObjectiveThe object of this study was to determine the effect of EAS (Equine-Assisted Services) on arthritis conditions, as measured by the sTnT (Skeletal troponin) and COMP (cartilage oligomeric matrix proteins) biomarkers, compared to an exercise attention control intervention. DesignThis was a secondary analysis of a randomized clinical trial comparing equine-assisted therapy to exercise education attention-control on cartilage and skeletal biomarkers in adults with arthritis. Twenty-one adults (Mage = 64 years) with arthritis who attended rheumatology clinics in the midwestern United States participated. ResultsNo changes were found in sTnT from baseline to week six within either intervention nor were there differences in changes between the two groups (p = 0.91). COMP increased from baseline to week six for both conditions, suggesting increased deterioration of cartilage and joints. Although the attention-control condition demonstrated larger increases in cartilage oligomeric matrix proteins level, compared to the EAS condition, these differences were not statistically (p = 0.58) or clinically significant (i.e., trivial effect, d = −0.16). When 3 outliers were removed, the differences in changes between EAT and attention-control group could be arguably of clinical significance (d = - 0.33), suggesting that the attention-control group demonstrated larger increases in levels of COMP than those in the EAS condition, though this difference was not statistically significant (p = 0.28). ConclusionAlthough equine-assisted therapy may reduce pain and improve quality of life for adults with arthritis, findings here are not fully corroborated with biomarkers.

Serial injections of 4% polyacrylamide hydrogel have no detrimental effects in equine joints following clinical, histologic, and synovial biomarker evaluation.

Polyacrylamide hydrogel (4% PAHG) is an inert viscoelastic supplement used to manage osteoarthritis in horses. Even with a prolonged clinical effect, horses may be administered multiple doses during their performance career. The effect of the serial 4% PAHG treatments is not known. The objectives of this study were to evaluate the clinical, histologic, and synovial fluid biomarker effects following serial administration of 4% PAHG in normal equine fetlock joints. 8 healthy horses. In a blinded, controlled in vivo study, horses received serial intra-articular injections of 4% PAHG (Noltrex Vet; Nucleus ProVets LLC) and contralateral 0.9% saline control on days 0, 45, 90, and 135. Treatment and control joints were randomly assigned. Synovial fluid was collected before administration of 4% PAHG or 0.9% saline on day 0 and at study completion for cellular and biomarker evaluation. Serial physical and lameness examinations were performed throughout the study. On day 240, gross examination and harvest of cartilage and synovial membrane for histology were completed. There were no histologic changes in articular cartilage or synovial fluid biomarkers. The 4% PAHG was seen on the surface of the synovium in 5 of 8 treated joints 105 days after the last treatment. There are minimal effects following serial injections of 4% PAHG on normal joints in horses following administration at 0, 45, 90, and 135 days, with final evaluation on day 240. Serial administration of intra-articular 4% PAHG in horses may provide long-term joint lubrication with no detrimental effects.

Biomarkers of Cartilage Composition.

Magnetic resonance imaging (MRI) has significantly advanced the understanding of osteoarthritis (OA) because it enables visualization of noncalcified tissues. Cartilage is avascular and nurtured by diffusion, so it has a very low turnover and limited capabilities of repair. Consequently, prevention of structural and detection of premorphological damage is key in maintaining cartilage health. The integrity of cartilage composition and ultrastructure determines its mechanical properties but is not accessible to morphological imaging. Therefore, various techniques of compositional MRI with and without use of intravenous contrast medium have been developed. Spin-spin relaxation time (T2) and spin-lattice relaxation time constant in rotating frame (T1rho) mapping, the most studied cartilage biomarkers, were included in the recent standardization effort by the Quantitative Imaging Biomarkers Alliance (QIBA) that aims to make compositional MRI of cartilage clinically feasible and comparable. Additional techniques that are less frequently used include ultrashort echo time with T2*, delayed gadolinium-enhanced MRI of cartilage (dGEMRIC), glycosaminoglycan concentration by chemical exchange-dependent saturation transfer (gagCEST), sodium imaging, and diffusion-weighted MRI.

ShapeMed-Knee: A Dataset and Neural Shape Model Benchmark for Modeling 3D Femurs.

Analyzing anatomic shapes of tissues and organs is pivotal for accurate disease diagnostics and clinical decision-making. One prominent disease that depends on anatomic shape analysis is osteoarthritis, which affects 30 million Americans. To advance osteoarthritis diagnostics and prognostics, we introduce ShapeMed-Knee, a 3D shape dataset with 9,376 high-resolution, medical-imaging-based 3D shapes of both femur bone and cartilage. Besides data, ShapeMed-Knee includes two benchmarks for assessing reconstruction accuracy and five clinical prediction tasks that assess the utility of learned shape representations. Leveraging ShapeMed-Knee, we develop and evaluate a novel hybrid explicit-implicit neural shape model which achieves up to 40% better reconstruction accuracy than a statistical shape model and implicit neural shape model. Our hybrid models achieve state-of-the-art performance for preserving cartilage biomarkers; they're also the first models to successfully predict localized structural features of osteoarthritis, outperforming shape models and convolutional neural networks applied to raw magnetic resonance images and segmentations. The ShapeMed-Knee dataset provides medical evaluations to reconstruct multiple anatomic surfaces and embed meaningful disease-specific information. ShapeMed-Knee reduces barriers to applying 3D modeling in medicine, and our benchmarks highlight that advancements in 3D modeling can enhance the diagnosis and risk stratification for complex diseases. The dataset, code, and benchmarks will be made freely accessible.

Early Castration in Horses Does Not Impact Osteoarticular Metabolism

The castration of stallions is traditionally performed after puberty, at around the age of 2 years old. No studies have focused on the effects of early castration on osteoarticular metabolism. Thus, we aimed to compare early castration (3 days after birth) with traditional castration (18 months of age) in horses. Testosterone and estradiol levels were monitored from birth to 33 months in both groups. We quantified the levels of biomarkers of cartilage and bone anabolism (CPII and N-MID) and catabolism (CTX-I and CTX-II), as well as of osteoarthritis (HA and COMP) and inflammation (IL-6 and PGE2). We observed a lack of parallelism between testosterone and estradiol synthesis after birth and during puberty in both groups. The extra-gonadal synthesis of steroids was observed around the 28-month mark, regardless of the castration age. We found the expression of estrogen receptor (ESR1) in cartilage and bone, whereas androgen receptor (AR) expression appeared to be restricted to bone. Nevertheless, with respect to osteoarticular metabolism, steroid hormone deprivation resulting from early castration had no discernable impact on the levels of biomarkers related to bone and cartilage metabolism, nor on those associated with OA and inflammation. Consequently, our research demonstrated that early castration does not disrupt bone and cartilage homeostasis.

254 Mineral Source Matters for Cartilage Development to Support Structural Integrity

Abstract Lameness is a welfare issue generally associated with increased growth rate. Objectives of this study were to 1) compare efficacy of inorganic (ITM) and organic trace mineral (OTM) sources on lameness incidence and effects on bone and cartilage biomarkers, and 2) determine if the biologically relevant biomarkers were detectable in saliva. Dietary treatments were fed for 70 d and included: 1) ITM sulfates, Zn-Cu-Mn supplemented at 120-20-40 mg/kg diet, and three OTMs supplemented at 80-10-20 Zn-Cu-Mn mg/kg diet, respectfully. The OTM treatments included a non-specific amino acid complex (Trt 2 – OTM complex), a glycinate (Trt 3 - OTM glycinate), and a metal methionine hydroxy analogue chelate (Trt 4 – OTM MMHAC) supplied as MINTREX trace minerals (Novus International, Inc., St Charles, MO). The study consisted of 144 barrows (56 kg initial BW; 36 pigs/trt; 18 pigs/pen on slatted concrete floors). A source of ractopamine hydrochloride (10 mg/kg) was fed the last 28 d of the trial to induce increased growth rate. Measurements included gait scoring (0-4; GS ≥ 2 defined as lame) and serum and saliva bone synthesis (osteocalcin), bone degradation (CTX1) and cartilage synthesis (P2CP), and cartilage degradative biomarkers (CTX2, C2C) and synthesis:degradation ratios measured at baseline, d 7, d 36 and d 70. Individual biomarkers were logarithmically transformed (base 10). Proc Mixed GLM procedure of SAS was performed on log-transformed data and means were determined using LSD test. Nonparametric comparisons (% lameness) were tested using Chi-squared analysis. A P-value < 0.05 was considered significant and P ≤ 0.10, a trend. As shown in Table, 1, lameness incidence was greatest for pigs fed ITM and OTM glycinate which was greater than OTM complex and MMHAC (P = 0.10). In general, there was good agreement between serum and saliva biomarkers, with pigs fed MMHAC having the greatest serum bone synthesis biomarker (osteocalcin) which differed from pigs fed OTM complex (P < 0.05). Cartilage synthesis concentrations (P2CP (serum and saliva); and P2CP/C2C and P2CP/CTX2 ratios (saliva) were also greatest for pigs fed MMHAC trace minerals (P < 0.05). Neither bone nor cartilage biomarkers were different between pigs fed ITM and OTM complex or glycinate. Osteocalcin was 10-fold less in saliva compared with serum. No treatment differences were observed in saliva for bone synthesis. The results demonstrated trace mineral source matters with respect to structural health. Significant differences between OTM sources were observed with MMHAC resulting in the highest bone and cartilage synthesis biomarker concentrations in serum and highest biomarkers for cartilage synthesis and synthesis:degradation ratios in saliva. Saliva appears to be a sensitive medium for measuring joint health biomarkers.

Changes in the Subchondral Bone, Visfatin, and Cartilage Biomarkers after Pharmacological Treatment of Experimental Osteoarthritis with Metformin and Alendronate.

Subchondral bone that has intense communication with the articular cartilage might be a potential target for pharmacological treatment in the early stages of osteoarthritis (OA). Considering the emerging data about the role of adipokines in the pathogenesis of OA, the administration of drugs that influence their level is also intriguing. Metformin and alendronate were administered in mice with collagenase-induced OA (CIOA) as a monotherapy and in combination. Safranin O staining was used for the assessment of changes in subchondral bone and articular cartilage. Before and after treatment, serum levels of visfatin and biomarkers of cartilage turnover (CTX-II, MMP-13, and COMP) were assessed. In the current study, the combined administration of alendronate and metformin in mice with CIOA led to the protection against cartilage and subchondral bone damage. In mice with CIOA, metformin led to a decrease in visfatin level. In addition, treatment with metformin, alendronate, or their combination lowered the level of cartilage biomarkers (CTX-II and COMP), while the level of MMP-13 was not influenced. In conclusion, personalized combination treatment in OA according to clinical phenotype, especially in the early stages of the disease, might lead to the identification of a successful disease-modifying therapeutic protocol in OA.

Poor correlation between biomarkers and MRI-detected joint damage in a cross-sectional study of persons with nonsevere hemophilia A (DYNAMO study)

BackgroundPersons with nonsevere hemophilia A (NSHA) experience less frequent joint bleeding than persons with severe hemophilia A, but may still develop joint damage. Biomarkers of cartilage and synovial remodeling can reflect ongoing pathologic processes that may precede or coincide with damage on joint imaging. If so, biomarkers may be an important diagnostic tool for joint damage in NSHA. ObjectiveTo assess the correlation between biomarkers and MRI-detected joint damage in persons with NSHA. MethodsIn a cross-sectional study, men with NSHA (factor VIII [FVIII], 2-35 IU/dL) were included. Participants underwent magnetic resonance imaging of elbows, knees, and ankles and blood and urine sampling for biomarker analysis on a single visit. The following biomarker(s) were analyzed in urine: CTX-II or serum: cartilage oligomeric matrix protein, chondroitin sulfate 846, vascular cell adhesion molecule 1, osteopontin (OPN), neo-epitope of MMP -mediated degradation of type II collagen, N-terminal propeptide of type II collagen, collagen type IV M, and propetide of type IV collagen. Spearman’s rank correlations were calculated between these biomarkers and the total International Prophylaxis Study group (IPSG) score, soft-tissue subscore, and osteochondral subscore. ResultsIn total, 48 persons with NSHA were included. Median age was 43 years (range, 24-55 years) and median FVIII was 10 IU/dL (IQR, 4-16 IU/dL). The median IPSG score was 4 (IQR, 2-9). Median IPSG soft-tissue subscores were 3 (IQR, 2-4) and osteochondral subscores were 0 (IQR, 0-4). No strong correlations were found between the studied biomarkers, total IPSG score, subsequent soft-tissue, and osteochondral subscores. ConclusionsIn this study, selected biomarkers indicative of different aspects of hemophilic arthropathy showed no consistent correlation with IPSG scores. This suggests that systemically measured biomarkers are currently not suitable for identifying milder joint damage in NSHA, as observed on magnetic resonance imaging.

Molecular Assessment of Healthy Pathological Articular Cartilages in Physically Active People: A Scoping Review.

Physiological aging triggers a cascade of negative effects on the human body and the human joint is only one of the several compartments affected by this irreversible and natural process. Osteoarthritis and cartilage degeneration can cause pain and disability; therefore, identifying the molecular processes underlying these phenomena and the biomarkers produced during physical activity is of critical importance. In the present review, the main goal was to identify and discuss the articular cartilage biomarkers analyzed in studies in which physical or sports activities were adopted and eventually to propose a standard operating procedure for the assessment. Articles collected from Pubmed, Web of Science, and Scopus were scrutinized to detect reliable cartilage biomarkers. The principal articular cartilage biomarkers detected in these studies were cartilage oligomeric matrix protein, matrix metalloproteinases, interleukins, and carboxy-terminal telopeptide. The articular cartilage biomarkers identified in this scoping review may aid in a better comprehension of where research on the topic is heading and offer a viable instrument for streamlining investigations on cartilage biomarker discovery.

Evaluation of articular cartilage wear against pyrolytic carbon in the context of spherical interposition shoulder arthroplasty

Metal shoulder hemiarthroplasty is known to cause failure due to glenoid cartilage erosion. Pyrolytic carbon (PyC), a non-metallic biomaterial, may be an attractive alternative due to its good general tribological characteristics and biocompatibility. We investigated the in vitro biotribological properties of PyC articulated against living cartilage for use as spherical shoulder interposition implant. The evaluation includes a comparison with the typically used cobalt‑chromium‑molybdenum alloy (CoCrMo) and zirconia toughened alumina (ZTA), a more recent biomaterial for hemiarthroplasty. The rate of cartilage degradation was assessed by means of cartilage wear biomarkers (glycosaminoglycans and hydroxyproline) in lubricant and histological changes of the cartilage superficial zone. In addition, the percentage of cell viability and metabolic activity of chondrocytes was assessed. The data revealed that PyC has similar tribological performance in terms of cell viability, cell metabolic activity, and tissue degradation compared to ZTA. Although not significant, CoCrMo affected chondrocyte metabolism and induced a thinner superficial layer with structural defects. There was a combined adsorption of phospholipids and biomarkers on the biomaterials; sGAGs adsorbed between 23 and 43% of the total concentration, and the adsorption rate of phospholipids increased significantly with friction. Biomaterial analysis is required to obtain the full picture of cartilage biomarker release and lubrication mechanisms. Our results suggest that PyC has good tribological performance and compares well with established biomaterials for hemiarthroplasty. It supports the use of PyC in spherical shoulder interposition implant as a viable alternative to conventional metal hemiarthroplasty. Further evaluation of the clinical performance of PyC is required.

The Effect of 13 Weeks Long-Distance Bicycle Riding on Inflammatory Response Indicators Related to Joint Cartilage and Muscle Damage.

This study was to investigate the effects of 13 weeks of long-distance cycling on biomarkers of joint cartilage, muscle damage and inflammation. All subjects in this study were seven participants of the “One Korea New-Eurasia Peace Cycle Expedition”, in which they rode cycles from Berlin, Germany to Seoul, Korea for thirteen weeks. The total course of the expedition was divided into three sub-courses: course 1 (from Berlin to Moscow), course 2 (from Moscow to Ulaanbaatar) and course 3 (from Ulaanbaatar to Seoul). All the selected participants rode 87.4 km/day (course 1), 70.4 km/day (course 2) and 57.6 km/day (course 3) on average, respectively. We collected their blood samples before the expedition in Seoul (S1), after course 1 in Moscow (M), after course 2 in Ulaanbaatar (U) and after the expedition in Seoul (S2), to analyze biomarkers of joint cartilage damage (Cartilage Oligomeric Matrix Protein; COMP), muscle damage (Creatine Phosphokinase; CPK, Lactate Dehydrogenase; LDH, Myoglobin), inflammation (Interleukin-6; IL-6, Interleukin-1β; IL-1β, Tumor Necrosis Factor-α; TNF-α, C-Reactive Protein; CRP) and stress hormone (Cortisol). According to this result, COMP (S1; 188.37 ± 46.68 ng/mL) showed a significant increase after the expedition course 1 (M; 246.69 ± 51.69 ng/mL, p = 0.012) and course 2 (U; 237.09 ± 62.57 ng/mL, p = 0.047), and recovered to the stable state after expedition course 3 (S2; 218.46 ± 34.78. p = 0.047). Biomarkers of muscle damage (CPK, LDH and Myoglobin) and inflammation (IL-6, IL-1β, TNF-α and CRP) were not significantly changed in all courses, but CRP (S1; 1.07 ± 0.76 ng/mL) showed a tendency to decrease after the expedition course 1 (M; 0.3 ± 0.1 mg/mL, p = 0.044). Lastly, the Cortisol level significantly increased in all courses (per p < 0.05), but the Cortisol level after expedition course 3 (S2; 21.00 ± 3.65 mg/mL) was lower than that of after the expedition course 1 (M; 24.23 ± 2.47 mg/mL, p = 0.028). In summary, it seems that repetitive and continuous 50−90 km/day of cycling can increase joint cartilage damage risk and stress hormone temporarily. However, this result suggests that the appropriate intensity of cycling for thirteen weeks does not increase physical damage, and rather enhances the human body to adapt to exercise training.

Comparison of clinical outcome, cartilage turnover, and inflammatory activity following either intra-articular or a combination of intra-articular with intra-osseous platelet-rich plasma injections in osteoarthritis knee: A randomized, clinical trial

BackgroundThe objective of the study was to determine the changes in clinical outcome (pain and knee activity) and assess bone/ cartilage biomarkers and inflammatory activity in persons with osteoarthritis (OA) knee following a single injection of intra-articular platelet-rich plasma (IA-PRP) and combination of intra-articular, intraosseous PRP (IA+IO-PRP). MethodsThis prospective, randomized, single-blind clinical trial was conducted at a tertiary care teaching hospital in India. Ninety-six persons with OA knee with a Kellgren-Lawrence score of 3 were randomized into three groups- Group-I (IA-PRP), Group-II (IA+IO-PRP)], Group-III, [intra-articular normal saline (IA-NS)]. The primary outcome was a visual analog scale (VAS) for pain. The secondary outcomes were the Knee Injury and Osteoarthritis Outcome Score (KOOS), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), bone/ cartilage turnover biomarkers [C-telopeptide (CTX-II), N-telopeptide (NTX-I), cartilage oligomeric matrix protein (COMP), N-terminal propeptide of collagen type-IIA (PIIANP), and hyaluronic acid (HA)], ultrasonography (USG) findings of the knee joint. The outcome measures were assessed at baseline, 6, and 12 weeks of follow-up. ResultsCompared to IA-NS injection, IA-PRP and IA+IO-PRP injections significantly improved VAS-pain and KOOS scores at 6 and 12 weeks. Furthermore, both PRP groups showed a significant reduction in ESR, CRP, and CTX-II at 12 weeks following PRP injections. In addition, at 12 weeks, the IA+IO-PRP group showed a significant reduction (p=0.009) in NTX-I level. Persons in the IA+IO-PRP group reported significant reductions in the synovial-effusion and infra-patellar bursitis. ConclusionsSignificant clinical improvements were noticed following IA-PRP and IA-IO-PRP injections compared to IA-NS injections. Both PRP groups reported a significant reduction in ESR, CRP, and CTX-II levels at 12 weeks. Persons in the IA+IO-PRP group reported significant changes in u-NTX-I level and knee-USG findings.

Donor age effects on in vitro chondrogenic and osteogenic differentiation performance of equine bone marrow- and adipose tissue-derived mesenchymal stromal cells

BackgroundBone marrow (BM)- and adipose tissue (AT)-derived mesenchymal stromal cells (MSCs) have shown potential as cell-based therapies for cartilage and bone injuries and are used increasingly in human and veterinary practice to facilitate the treatment of orthopedic conditions. However, human and rodent studies have documented a sharp decline in chondrogenic and osteogenic differentiation potential with increasing donor age, which may be problematic for the important demographic of older orthopedic patients. The aim of this study was to identify the effect of donor age on the chondrogenic and osteogenic differentiation performance of equine BM- and AT-MSCs in vitro.BM- and AT-MSCs and dermal fibroblasts (biological negative control) were harvested from horses in five different age groups (n = 4, N = 60); newborn (0 days), yearling (15–17 months), adult (5–8 years), middle-aged (12–18 years), and geriatric (≥ 22 years). Chondrogenic differentiation performance was assessed quantitatively by measuring pellet size, matrix proteoglycan levels, and gene expression of articular cartilage biomarkers. Osteogenic differentiation performance was assessed quantitatively by measuring alkaline phosphatase activity, calcium deposition, and gene expression of bone biomarkers.ResultsChondrogenic and osteogenic differentiation performance of equine BM- and AT-MSCs declined with increasing donor age. BM-MSCs had a higher chondrogenic differentiation performance. AT-MSCs showed minimal chondrogenic differentiation performance in all age groups. For osteogenesis, alkaline phosphatase activity was also higher in BM-MSCs, but BM-MSCs calcium deposition was affected by donor age earlier than AT-MSCs. Chondrogenic and osteogenic differentiation performance of BM-MSCs exhibited a decline as early as between the newborn and yearling samples. Steady state levels of mRNA encoding growth factors, chondrogenic, and osteogenic biomarkers were lower with increasing donor age in both MSC types.ConclusionsThe data showed that chondrogenic and osteogenic differentiation performance of equine BM-MSCs declined already in yearlings, and that AT-MSCs showed minimal chondrogenic potential, but were affected later by donor age with regards to osteogenesis (calcium deposition). The results highlight the importance of donor age considerations and MSC selection for cell-based treatment of orthopedic injuries and will help inform clinicians on when to implement or potentially cryopreserve cells. Moreover, the study provides molecular targets affected by donor age.

Association between cartilage biomarker level and functional outcome in knee osteoarthritis patients receiving dextrose prolotherapy: a cross-sectional study

Background: Knee osteoarthritis (KOA) is a degenerative joint disease with relatively high prevalence globally and is one of the leading causes of disability in the elderly population. Dextrose prolotherapy (DPT) has been proven effective in improving functional outcomes in knee osteoarthritis. The effect of hypertonic dextrose on cartilage biomarkers has not been evaluated. Purpose: To evaluate the association between a cartilage biomarker and changes in clinical outcomes among patients with KOA who received dextrose prolotherapy (DPT). Patients and methods: This study was conducted with a cross-sectional design. Twenty-six participants received DPT at weeks 1, 5, and 9. Our primary measures were urinary c-terminal telopeptides of type II collagen (uCTX-II), measured by an enzyme-linked immunosorbent assay (ELISA), and the WOMAC score, measured at baseline and week 12. Results: There were significant improvements in all WOMAC subscales and uCTX-II levels after DPT. There is no significant correlation between biomarker levels with the WOMAC score as a functional outcome indicator in KOA after DPT (p &gt; 0.05), but there are positive correlations between pain, functional, total WOMAC score, and uCTX-II. Conclusion: DPT may reduce cartilage degradation and improve functional outcomes in osteoarthritic knees. Significant drops in uCTX-II levels can affect functional outcomes, especially pain, functional and total WOMAC scores.

Dose-response relationship of in vivo ambulatory load and mechanosensitive cartilage biomarkers-The role of age, tissue health and inflammation: A study protocol.

ObjectiveTo describe a study protocol for investigating the in vivo dose-response relationship between ambulatory load magnitude and mechanosensitive blood markers of articular cartilage, the influence of age, cartilage tissue health and presence of inflammation on this relationship, and its ability to predict changes in articular cartilage quality and morphology within 2 years.DesignProspective experimental multimodal (clinical, biomechanical, biological) data collection under walking stress and three different load conditions varied in a randomized crossover design.Experimental protocolAt baseline, equal numbers of healthy and anterior cruciate ligament injured participants aged 20–30 or 40–60 years will be assessed clinically and complete questionnaires regarding their knee health. Biomechanical parameters (joint kinetics, joint kinematics, and surface electromyography) will be recorded while performing different tasks including overground and treadmill walking, single leg balance and hopping tasks. Magnetic resonance images (MRI) of both of knees will be obtained. On separate stress test days, participants will perform a 30-minute walking stress with either reduced (80% body weight (BW)), normal (100%BW) or increased (120%BW) load. Serum blood samples will be taken immediately before, immediately after, 30, 120 and 210 minutes after the walking stress. Concentration of articular cartilage blood biomarkers will be assessed using enzyme linked immunosorbent assays. At 24-month follow-up, participants will be again assessed clinically, undergo an MRI, complete questionnaires, and have a blood sample taken.ConclusionThe study design provides a standardized set up that allows to better understand the influence of ambulatory load on articular cartilage biomarkers and thereby extend current knowledge on in vivo cartilage metabolism and mechanosensitivity. Further, this study will help to elucidate the prognostic value of the load-induced cartilage biomarker response for early articular cartilage degeneration.Trial registrationThe protocol was approved by the regional ethics committee and has been registered at clinicaltrials.gov (NCT04128566).

The alarmins high mobility group box protein 1 and S100A8/A9 display different inflammatory profiles after acute knee injury

To compare the concentrations of high mobility group box 1 protein (HMGB1) and S100A8/A9 in synovial fluid between patients with knee injuries and osteoarthritis (OA), and knee healthy subjects. To investigate associations of alarmin levels with different joint injuries and with biomarkers of inflammation, Wnt signaling, complement system, bone and cartilage degradation. HMGB1 and S100A8/A9 were measured in synovial fluid by immunoassays in patients with knee injuries, with OA and from knee healthy subjects, and were related to time from injury and with biomarkers obtained from previous studies. Hierarchical cluster and enrichment analyses of biomarkers associated to HMGB1 and S100A8/A9 were performed. The synovial fluid HMGB1 and S100A8/A9 concentrations were increased early after knee injury; S100A8/A9 levels were negatively associated to time after injury and was lower in the old compared to recent injury group, while HMGB1 was not associated to time after injury. The S100A8/A9 levels were also increased in OA. The initial inflammatory response was similar between the alarmins, and HMGB1 and S100A8/A9 shared 9 out of 20 enriched pathways. The alarmins displayed distinct response profiles, HMGB1 being associated to cartilage biomarkers while S100A8/A9 was associated to proinflammatory cytokines. HMGB1 and S100A8/A9 are increased as an immediate response to knee trauma. While they share many features in inflammatory and immunoregulatory mechanisms, S100A8/A9 and HMGB1 are associated to different downstream responses, which may have impact on the OA progression after acute knee injuries.

Knee Cartilage and Subchondral Bone Evaluations by Magnetic Resonance Imaging Correlate with Histological Biomarkers in an Osteoarthritis Rabbit Model.

ObjectiveTo evaluate pathological changes in cartilage and subchondral bone MRI biomarkers in a rabbit model of osteoarthritis (OA) and correlate these with histological variations.DesignTransection of the anterior cruciate ligament was performed on the right knee of eighteen 12-week-old New Zealand white rabbits to induce OA. 3-Tesla MR images were obtained from 18 healthy control knees (left) and 18 knees with OA (right). Imaging biomarkers included volume, thickness, T1 and T2* cartilage parametric maps, and several subchondral bone features: bone volume to total volume ratio, trabecular thickness, trabecular spacing, trabecular number (TbN), 2D and 3D fractal dimensions, and quality of trabecular score (QTS). Microscopic analysis of the lateral femoral condyles was set as the ground truth.ResultsWhen healthy and osteoarthritic knees were compared, significant differences were seen in the T1 and T2* values of the femur and tibia cartilage and in the subchondral bone volume to total volume, TbN, and QTS of both the lateral and medial aspects of the femur and tibia. Histological findings revealed significant osteoarthritic changes between healthy and osteoarthritic knees in stain, structure, chondrocyte density, total score, and subchondral bone biomarker levels. A positive correlation was found between histological staining, structure, chondrocyte density, and total score variables in T1 and T2* cartilage biomarkers. A negative correlation was observed between histological subchondral bone variables and magnetic resonance D2D and QTS biomarkers.ConclusionQuantification of several cartilage and subchondral bone imaging biomarkers in a rabbit model of OA allows the detection of significant changes, which are correlated with histological findings.

Effect of moderate forced physical activity on behaviour, lameness and osteochondrosis in growing pigs from two divergent lines selected for feed efficiency

In pig farming, physical constraints and genetic selection for high production are risk factors for the development of leg disorders, such as degraded locomotor activity. Interactions between both factors need to be explored. The study was carried out on two replicates of 80 pure-bred Large White growing-finishing pigs from the 8th generation of two divergent lines selected for low and high residual feed intake (LRFI, HRFI). Each replicate included 40 LRFI pigs and 40 HRFI pigs, housed on partly slatted flooring in a room equipped with a sorter allowing access to electronic self-feeders during two replicates. Ear tags determined the side of the room to which the pigs were oriented after the sorter exit and the distance back to the sorter (short: spontaneous activity, long: forced activity (FA)). Lameness was assessed individually weekly using visual gait scoring. At slaughter (weight of 100 kg), postmortem quantification of osteochondrosis (OC) lesions was performed on both the proximal and distal extremities of the humerus and femur. Low RFI pigs showed a lower feed conversion ratio (P < 0.001). They also showed lower individual numbers of sorter crossings per day and a lower proportion of standing pigs, which confirmed their lower physical activity. Forced activity clearly increased the number of sorter crossings/d/pig (P < 0.001), and the magnitude of the effect of FA was clearly lower in LRFI pigs than in HRFI pigs. The occurrence of gait was low (less than 9% of recorded scores). The proportion of scores classified as stiffness was higher for LRFI pigs than in HRFI pigs (P < 0.0001). The average lameness score was also higher for LRFI pigs and lower with FA (P < 0.05). The pigs of the LRFI line showed higher OC scores on both the proximal humerus and femur (P < 0.001) and lower OC scores on the distal humerus with surface evaluation (P < 0.05). The carcasses of LRFI pigs were heavier with a higher lean meat percentage (P < 0.001). Most OC scores were unaffected by FA. Only the OC scores of the distal femur (slice method) were higher with increased activity in LRFI pigs, whereas they were lower in HRFI pigs (P < 0.05). Seric biomarkers of cartilage synthesis and degradation were higher for pigs from the LRFI line, but no correlation could be observed between individual OC scores and cartilage biomarker contents.

Relationship between different serum cartilage biomarkers in the acute response to running and jumping in healthy male individuals

The effect of physical activity on serum cartilage biomarkers is largely unknown. The purpose of the study was to systematically analyze the acute effect of two frequently used exercise interventions (running and jumping) on the correlation of seven serum biomarkers that reflect cartilage extracellular matrix metabolism. Fifteen healthy male volunteers (26 ± 4 years, 181 ± 4 cm, 77 ± 6 kg) participated in the repeated measurement study. In session 1, the participants accomplished 15 × 15 series of reactive jumps within 30 min. In session 2, they ran on a treadmill (2.2 m/s) for 30 min. Before and after both exercise protocols, four blood samples were drawn separated by 30 min intervals. Serum concentrations of seven biomarkers were determined: COMP, MMP-3, MMP-9, YKL-40, resistin, Coll2-1 and Coll2-1 NO2. All biomarkers demonstrated an acute response to mechanical loading. Both the COMP and MMP-3 responses were significantly (p = 0.040 and p = 0.007) different between running and jumping (COMP: jumping + 31%, running + 37%; MMP-3: jumping + 14%, running + 78%). Resistin increased only significantly (p < 0.001) after running, and Coll2-1 NO2 increased significantly (p = 0.001) only after jumping. Significant correlations between the biomarkers were detected. The relationships between individual serum biomarker concentrations may reflect the complex interactions between degrading enzymes and their substrates in ECM homeostasis.

ASSOCIATIONS BETWEEN PHYSICAL ACTIVITY, SELF-REPORTED JOINT FUNCTION AND MOLECULAR BIOMARKERS IN WORKING AGE INDIVIDUALS WITH HIP AND/OR KNEE OSTEOARTHRITIS

Purpose: Previous research has suggested an association between physical activity (PA), joint function and molecular biomarkers but more studies are needed. The aim of this study was to explore the associations between PA or self-reported joint function and molecular biomarkers of cartilage and inflammation in individuals with hip and/or knee osteoarthritis (OA). Specific objectives were to explore the correlations between i) change over three months in self-reported PA/joint function and change in molecular biomarkers (ii) objectively measured PA and molecular biomarkers measured at three month follow-up.