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Background This study aimed to investigate the expression of vascular endothelial growth factor (VEGF) in cruciate ligaments from patients with osteoarthritis (OA). It was hypothesized that the expression level of VEGF is associated with the extent of degeneration of the cruciate ligaments. Methods Remnants of anterior cruciate ligaments (ACLs) from patients with acute ACL injury due to trauma, and ACLs and posterior cruciate ligaments (PCLs) from patients with primary OA were assessed histologically. Samples were immunohistochemically stained with VEGF and tenomodulin, and immunopositive cells were quantitatively assessed by the histological grades of ligament degeneration. Results Histological analysis showed significant degeneration of the ACLs from OA patients compared with trauma patients, with increased expression of VEGF correlating with higher grades of degeneration. Conversely, tenomodulin expression was lower in more degenerated cruciate ligaments. The percentage of VEGF-positive cells was correlated inversely with that of tenomodulin-positive cells. Conclusions Increased VEGF expression is associated with degeneration of cruciate ligaments in patients with osteoarthritis of the knee.

Background The Anterior Cruciate Ligament (ACL) plays a critical role in maintaining the musculoskeletal stability of the knee. Its injury has been linked to an increased risk of developing osteoarthritis. This study aims to identify cross-species responses to ACL rupture providing insights on its molecular basis. We analyzed five publicly available transcriptomic datasets from Homo sapiens , Mus musculus , Canis lupus familiaris , and Oryctolagus cuniculus . Differential gene expression analysis was performed for each dataset, producing a genome-wide transcriptional signature of fold-change significance for individual genes. Stouffer’s method was used to integrate the results, identifying genes significantly deregulated across all species. Additionally, gene-set enrichment analysis revealed pathways that were consistently upregulated or downregulated. Results A positive correlation in expression was observed between human and the other three species (r 2  = 0.177–0.305, p -value ≤ 2.7 × 10 − 113 ), identifying 210 genes as the most consistently up- and down-regulated in response to ACL rupture ( p -adjusted ≤ 1.27 × 10 − 23 ). These genes are primarily involved in cellular mitosis, collagen pathways, and cartilage development. Furthermore, 60 pathways were found to be significantly up- or down-regulated across all species ( p -adjusted ≤ 4.57 × 10 − 4 ). Among these, the upregulation of inhibition of bone mineralization ( p -adjusted ≤ 2.99 × 10 − 6 ) aligns with previous findings on the reduction of subchondral bone mineral density following ACL rupture. Conclusions This study highlights that distinct species exhibit common molecular responses to ACL rupture, underscoring the value of mice, dogs, and rabbits as potential translational model organisms for ACL rupture research. Furthermore, the identified genes and pathways highlight the molecular mechanisms underlying ACL rupture.

The purpose of this study was to evaluate matrix metalloproteinases (MMP) -2 and MMP-3 in serum, and keratinocyte-derived chemoattractant (KC), interleukin 8 (IL-8) and monocyte chemoattractant 1 (MCP-1) in synovial fluid (SF) as stifle osteoarthritis (OA) biomarkers in dogs. Dogs with naturally occurring cranial cruciate ligament (CrCL) rupture (OA group) and healthy controls were recruited. Stifles with CrCL deficiency were surgically stabilized. Serum, SF, and synovial biopsy samples were collected from the OA group preoperatively, whereas samples were collected once from control dogs. A blinded veterinary pathologist graded synovial biopsies. Serum and SF analyses were performed using xMAP technology. General linear regression was used for statistical comparisons of serum biomarkers, and mixed linear regression for SF biomarkers and temporal concentration changes. The overall discriminative ability was quantified using area under curve (AUC). Spearman’s correlation coefficient was used to assess correlations between synovial histology grades and the biomarkers. Samples from 62 dogs in the OA group and 50 controls were included. The MMP-2 and MMP-3 concentrations between the OA and control groups were not significantly different, and both with an AUC indicating a poor discriminative ability. All three SF biomarker concentrations were significantly different between the OA group and controls ( P <0.05). The MCP-1 was the only biomarker showing an acceptable discriminative performance with an AUC of 0.91 (95% confidence interval: 0.83–0.98). The sum of the inflammatory infiltrate score was significantly correlated with all three SF biomarkers ( P <0.01). Summed synovial stroma, and all scores combined were significantly correlated with IL-8 and MCP-1 concentrations ( P <0.003), and the summed synoviocyte scores were significantly correlated with MCP-1 concentrations ( P <0.001). Correlations between MCP-1 concentrations and synovial histopathologic grading and its discriminative ability suggest its potential as a synovitis biomarker in canine stifle OA associated with CrCL rupture.

A rupture of the anterior cruciate ligament (ACL) is the most common knee ligament injury. Current applied reconstruction methods have limitations in terms of graft availability and mechanical properties. A new approach could be the use of a tissue engineering construct that temporarily reflects the mechanical properties of native ligament tissues and acts as a carrier structure for cell seeding. In this study, embroidered scaffolds composed of polylactic acid (PLA) and poly(lactic-co-ε-caprolactone) (P(LA-CL)) threads were tested mechanically for their viscoelastic behavior under in vitro degradation. The relaxation behavior of both scaffold types (moco: mono-component scaffold made of PLA threads, bico: bi-component scaffold made of PLA and P(LA-CL) threads) was comparable to native lapine ACL. Most of the lapine ACL cells survived 32 days of cell culture and grew along the fibers. Cell vitality was comparable for moco and bico scaffolds. Lapine ACL cells were able to adhere to the polymer surfaces and spread along the threads throughout the scaffold. The mechanical behavior of degrading matrices with and without cells showed no significant differences. These results demonstrate the potential of embroidered scaffolds as an ACL tissue engineering approach.

Dogs are commonly affected with cruciate ligament rupture (CR) and associated osteoarthritis (OA), and frequently develop a second contralateral CR. Platelet rich plasma (PRP) is a component of whole blood that contains numerous growth factors, which in combination with a collagen scaffold may act to promote bioenhanced primary repair of ligament. This study tested the hypothesis that treatment of partial stable CR stifles with an intra-articular collagen scaffold and PRP would decrease the disease progression, synovitis and risk of complete CR over a 12-month study period. We conducted a prospective cohort study of 29 client-owned dogs with an unstable stifle due to complete CR and stable contralateral stifle with partial CR. All dogs were treated with tibial plateau leveling osteotomy (TPLO) on the unstable stifle and a single intra-articular application of PRP-collagen in the stable partial CR stifle. Dogs were evaluated at the time of diagnosis, and at 10-weeks and 12-months after treatment. We evaluated correlation between both development of complete CR and time to complete CR with diagnostic tests including bilateral stifle radiographs, 3.0 Tesla magnetic resonance (MR) imaging, and bilateral stifle arthroscopy. Additionally, histologic evaluation of synovial biopsies, C-reactive protein (CRP) concentrations in serum and synovial fluid, and synovial total nucleated cell count, were determined. Results indicated that a single application of PRP-collagen in partial CR stifles of client owned dogs is not an effective disease-modifying therapy for the prevention of progression to complete CR. Radiographic effusion, arthroscopic evaluation of cranial cruciate ligament (CrCL) damage, and MR assessment of ligament fiber tearing in partial CR stifles correlated with progression to complete CR over the 12-month follow-up period. We determined that the best predictive model for development of complete CR in PRP-collagen treated partial CR stifles included variables from multiple diagnostic modalities.

Backgrounds: In this research, we want to find out whether extracellular vesicles (EVs) from adipose-derived mesenchymal stem cells (MSCs) can improve ligament–bone integration after primary Anterior Cruciate Ligament (ACL) repair by performing immunological and biomechanical tests. Methods: All of the rabbits underwent ACL resection at the proximal attachment to the femur bone, and then were divided into four groups. We performed an ELISA examination from the tissue at the bone–ligament interface of iNOS, CD206, MMP-3, and TIMP-1 to evaluate their levels at the inflammatory stage at the end of the first week. Immunoexpression of type I and III collagen and failure load biomechanical tests were performed at the end of the sixth week. Result: The group that underwent ACL repair with EVs augmentation had significantly higher levels of CD206, significantly lower MMP-3 levels, and significantly higher TIMP-1 levels in the first week. The iNOS levels in the group that underwent ACL repair with EVs augmentation were significantly different compared to the control group that did not receive any. The number of type I collagen fibers and the failure load levels in the group that underwent ACL repair with EVs augmentation were significantly higher. Conclusions: EVs from adipose-derived MSCs can improve the outcome of primary ACL repair in rabbits by regulating the inflammatory process during the healing period.

Anterior cruciate ligaments (ACL) injuries represent a major risk factor for early osteoarthritis (OA). To evaluate the prevalence and 4-year progression of knee OA measured with 3T MR-imaging in individuals with ruptured, reconstructed or normal ACL and to assess the impact of thigh muscle characteristics. A total of 54 knees (23/54 male, 31/54 female) were recruited from the Osteoarthritis Initiative (OAI). At baseline, 15/54 subjects had prevalent ACL ruptures and 15/54 subjects had prevalent ACL reconstruction (24/54 normal ACL). Western Ontario and McMasters Universities Arthritis Index (WOMAC) scores, Physical Activity Scores of the Elderly (PASE) and thigh muscle characteristics including strength, fat infiltration (Goutallier score) and thigh muscle cross-sectional area (CSA) MR measurements were obtained at baseline. Whole-organ MR-imaging Scores (WORMS) were obtained at baseline and at a 4-year follow-up time-point. Multivariate regression models, adjusting for covariates (age, gender, body mass index), were used for statistical analysis. At baseline, subjects with prevalent ACL ruptures had worse WORMS total scores (mean±SEM, 44.1±3.5) than subjects with ACL reconstruction (30.8±4.0; P = 0.015) and worse than subjects with normal ACL (21.3±3.0; P<0.001). Cartilage scores were worse in both femorotibial compartments in ACL injured knees than in knees with normal ACL (P<0.05). Knees with ACL reconstruction showed an increased degeneration of the medial meniscus (P = 0.036), cartilage degeneration at the medial femoral condyle (P = 0.011). In a multivariate regression model, including both ACL groups and total muscle characteristics as influence parameters, high thigh muscle CSA, high muscle/ fat ratio and low Goutallier scores were associated with less degenerative changes at the knee, independent of ACL status. Knees with ACL reconstruction showed an increased progression of cartilage degeneration at the medial tibia compared to the normal ACL group (P = 0.027). High thigh muscle CSA is associated with less degenerative changes at the knee, independent of the ACL status and may potentially be advantageous in the prevention of early OA.

Lubricin is an important boundary lubricant and chondroprotective glycoprotein in synovial fluid. Both increased and decreased synovial fluid lubricin concentrations have been reported in experimental post-traumatic osteoarthritis (PTOA) animal models and in naturally occurring joint injuries in humans and animals, with no consensus about how lubricin is altered in different species or injury types. Increased synovial fluid lubricin has been observed following intra-articular fracture in humans and horses and in human late-stage osteoarthritis; however, it is unknown how synovial lubricin is affected by knee-destabilizing injuries in large animals. Spontaneous rupture of cranial cruciate ligament (RCCL), the anterior cruciate ligament equivalent in quadrupeds, is a common injury in dogs often accompanied by OA. Here, clinical records, radiographs, and synovial fluid samples from 30 dogs that sustained RCCL and 9 clinically healthy dogs were analyzed. Synovial fluid lubricin concentrations were nearly 16-fold greater in RCCL joints as compared to control joints, while IL-2, IL-6, IL-8, and TNF-α concentrations did not differ between groups. Synovial fluid lubricin concentrations were correlated with the presence of radiographic OA and were elevated in three animals sustaining RCCL injury prior to the radiographic manifestation of OA, indicating that lubricin may be a potential biomarker for early joint injury.

Runx2 is a powerful osteo-inductive factor and adipose-derived stem cells (ADSCs) are multipotent. However, it is unknown whether Runx2-overexpressing ADSCs (Runx2-ADSCs) could promote anterior cruciate ligament (ACL) reconstruction. We evaluated the effect of Runx2-ADSCs on ACL reconstruction in vitro and in vivo . mRNA expressions of osteocalcin (OCN), bone sialoprotein (BSP) and collagen I (COLI) increased over time in Runx2-ADSCs. Runx2 overexpression inhibited LPL and PPARγ mRNA expressions. Runx2 induced alkaline phosphatase activity markedly. In nude mice injected with Runx2-ADSCs, promoted bone formation was detected by X-rays 8 weeks after injection. The healing of tendon-to-bone in a rabbit model of ACL reconstruction treated with Runx2-ADSCs, fibrin glue only and an RNAi targeting Runx2, was evaluated with CT 3D reconstruction, histological analysis and biomechanical methods. CT showed a greater degree of new bone formation around the bone tunnel in the group treated with Runx2-ADSCs compared with the fibrin glue group and RNAi Runx2 group. Histology showed that treatment with Runx2-ADSCs led to a rapid and significant increase at the tendon-to-bone compared with the control groups. Biomechanical tests demonstrated higher tendon pullout strength in the Runx2-ADSCs group at early time points. The healing of the attachment in ACL reconstruction was enhanced by Runx2-ADSCs.

Objectives. To examine the metabolic profiles alterations of synovial fluids from anterior cruciate ligament- (ACL-) injured rabbit knees at early stage and analyze the correlation with T2 relaxation times of cartilage and meniscus. Methods. The right knees of 15 rabbits were selected for the construction of ACL injury models, whereas the contralateral knees served as control group. After 4 weeks, both knees were examined by MRI with quantitative T2 mapping sequence, and the T2 relaxation times of cartilage and meniscus were measured. Then, the synovial fluids were obtained from both knee capsules and performed liquid chromatography-mass spectrometry analysis (LC-MS). Results. The T2 relaxation times of cartilage and meniscus in ACL-injured knees were significantly higher than those in control knees (Cartilage: 41.52 ± 2.98 ms vs 36.02 ± 2.71 ms, P < 0.001; Meniscus: 33.35 ± 3.57 ms vs 27.27 ± 2.10 ms, P < 0.001). Twenty-eight differential metabolites were identified based on a total of 1569 detected signatures between ACL-injured knees and control knees. These differential metabolites primarily implied perturbations in the fluxes of lipids and steroid-based compounds. The Linear regression analysis demonstrated satisfactory correlations between glycerophospholipid metabolism and T2 relaxation times of both cartilage and meniscus in ACL-injured knees (R2 = 0.8204 and 0.8197, respectively). Conclusion. ACL injury of rabbit knees resulted in elevated T2 relaxation times of cartilage and meniscus and perturbed metabolism of various lipids and steroids in synovial fluids, particularly glycerophospholipids. Glycerophospholipid metabolism related compounds could serve as potential biomarkers for early degenerative changes of cartilage and meniscus after ACL injury.