VEGF-A is associated with early degenerative changes in cartilage and subchondral bone.

Paired cartilage and subchondral bone of subjects with no clinical history of joint disorders were analyzed to determine whether antioxidant enzymes, inflammatory cytokines and growth factors can be linked to a pre-osteoarthritis. Tissue explants were phenotyped according to Osteoarthritis Research Society International grading and micro-computed tomography, and also screened for the expression of several markers using quantitative polymerase chain reaction. The expression of these same genes was measured in SW1353 cells treated with hydrogen peroxide, to gain insight into the pathways involved with oxidative stress responses. Vascular endothelial growth factor A (VEGF-A) was up-regulated in the cartilage samples that showed early cartilage or bone degeneration. Oxidative stress in chondrocytes provoked up-regulation of interleukin-1ß, interleukin-6, aggrecan, and SRY-box containing gene 9. Our results confirm the hitherto evidence of the deteriorating effects of the oxidative stress on cartilage and suggest the link between VEGF-A and pre-osteoarthritis.

Using 3D MRI Bone Shape to Predict Pre-Osteoarthritis of the Knee 2 Years After Anterior Cruciate Ligament Reconstruction.

BACKGROUND: Anterior cruciate ligament (ACL) injury increases risks for osteoarthritis (OA), a poorly modifiable and disabling condition. Joint changes of potentially reversible pre-OA have been described just 2 years after ACL reconstruction (ACLR) when early bone shape changes have also been reported. PURPOSE: This study evaluates relationships between interlimb differences in tibiofemoral bone shape derived from statistical shape modeling (SSM) of magnetic resonance imaging (MRI) and participant factors on patient-reported outcomes 2 years after unilateral ACLR. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: SSM-derived tibiofemoral bone shape and subchondral bone area were assessed from bilateral knee MRI scans of 72 participants with unilateral ACLR (mean age, 34 ± 11 years; 32 women) and compared with a reference cohort of 398 older individuals without OA (mean age, 50 ± 3 years; 213 women). Multivariable logistic regression models examined relationships between participant and surgical factors with interlimb differences in bone shapes or subchondral bone areas. Relationships between patient-reported outcomes and the interlimb differences in bone shape and subchondral area were examined using similar models. RESULTS: Bone shape scores and subchondral bone areas were greater (more OA-like) in ACLR knees than uninjured contralateral knees in every bone metric tested (P≤ .001). Interlimb differences in femur shape scores of participants with ACLR were 65% greater (P < .001) than those of the significantly older reference cohort. Taller height, medial meniscal tears, and decreasing age were associated with larger interlimb differences in shape scores and subchondral areas (P < .05). Bone-patellar tendon-bone (BPTB) autograft recipients demonstrated greater interlimb subchondral area differences compared with allograft recipients (P < .05). Interlimb differences for hamstring autograft recipients did not differ from those with BPTB or allograft. Greater interlimb differences in medial femur subchondral areas were associated with worse patient-reported Knee injury and Osteoarthritis Outcome Score Symptoms (R = 0.27; P = .040). CONCLUSION: Even in the absence of radiographic OA, just 2 years after unilateral ACLR patients showed greater bone shape scores and subchondral areas consistent with pre-OA in their ACLR knees. Furthermore, greater medial femur bone areas were weakly associated with worse symptoms. Patients who are younger, are taller, have meniscal tears, or have BPTB grafts may be at increased risk for bony asymmetries 2 years after ACLR.

Can we afford to ignore the biology of joint healing and graft incorporation after ACL reconstruction?

Anterior cruciate ligament (ACL) reconstruction is successful at restoring stability to return ACL injured patients to high-demand work, sports, and recreational activities. The development of posttraumatic osteoarthritis (OA) in roughly half of patients just 10-15 years after ACLR highlight the need to improve clinical care pathways. Graft failure and reinjury rates, which further increase OA risk, also remain high for younger and more active patients. The biological components of joint recovery and graft incorporation, therefore, impact short- and long-term clinical outcomes. Biochemical and magnetic resonance imaging (MRI) data show substantial compromise of articular cartilage metabolism and matrix composition after ACL injury and reconstructive surgery suggesting a potential need for activity modulation in early recovery. Furthermore, joint recovery is variable with compositional MRI studies showing progressive cartilage degeneration 1 and 2 years after ACLR. Biopsy and MRI studies also show high variability in ACL graft characteristics within the 1st year after ACLR followed by continued graft maturation into the 2nd year and beyond. To improve the care of ACL injured patients, there is a critical need for clinical attention and scientific inquiry into timing the reintroduction of higher load activities in relationship to neuromuscular recovery, joint biology, and graft maturation. In addition to symptomatic and mechanical recovery, development and validation of biological markers for joint and cartilage homeostasis as well as ACL graft healing are needed for personalized decision making on rehabilitation needs, reduction of OA risk, and resumption of athletic, recreational, and vocational activities.

Current and Future Advanced Imaging Modalities for the Diagnosis of Early Osteoarthritis of the Hip.

Hip osteoarthritis (OA) can be idiopathic or develop secondary to structural joint abnormalities of the hip joint (alteration of normal anatomy) and/or due to a systemic condition with joint involvement. Early osteoarthritic changes to the hip can be completely asymptomatic or may cause the development hip symptomatology without evidence of OA on radiographs. Delaying the progression of hip OA is critical due to the significant impact of this condition on the patient's quality of life. Pre-OA of the hip is a newly established term that is often described as the development of signs and symptoms of degenerative hip disease but no radiographic evidence of OA. Advanced imaging methods can help to diagnose pre-OA of the hip in patients with hip pain and normal radiographs or aid in the surveillance of asymptomatic patients with an underlying hip diagnosis that is known to increase the risk of early OA of the hip. These methods include the delayed gadolinium-enhanced magnetic resonance imaging (MRI) of cartilage (dGEMRIC), quantitative magnetic resonance imaging (qMRI- T1rho, T2, and T2* relaxation time mapping), 7-Tesla MRI, computed tomography (CT), and optical coherence tomography (OCT). dGEMRIC proved to be a reliable and accurate modality though it is limited by the significant time necessary for contrast washout between scans. This disadvantage is potentially overcome by T2 weighted MRIs, which do not require contrast. 7-Tesla MRI is a promising development for enhanced imaging resolution compared to 1.5 and 3T MRIs. This technique does require additional optimization and development prior to widespread clinical use. The purpose of this review was to summarize the results of translational and clinical studies investigating the utilization of the above-mentioned imaging modalities to diagnose hip pre-OA, with special focus on recent research evaluating their implementation into clinical practice.

Protein Levels and Microstructural Changes in Localized Regions of Early Cartilage Degeneration Compared with Adjacent Intact Cartilage.

OBJECTIVE: It was hypothesized that the respective protein profiles of bovine cartilage from sites of localized mild to moderate (GI to GII) degeneration versus adjacent sites of intact tissue would vary in accordance with the tissue microstructural changes associated with a pre-osteoarthritic state. METHODS: A total of 15 bovine patellae were obtained for this study. Paired samples of tissue were collected from the lateral region of each patella. If the patella contained a site of degeneration, a paired tissue set involved taking one sample each from the degenerated site and the intact tissue adjacent to it. Sufficient tissue was collected to facilitate 2 arms of investigation: microstructural imaging and proteome analysis. The microstructural analysis used a bespoke tissue preparation technique imaged with differential interference contrast optical microscopy to assess fibrillar scale destructuring and underlying bone spicule formation. An iTRAQ-based proteome analysis was performed using liquid chromatography-tandem mass spectrometry to identify the differential levels of proteins across the intact and degenerated cartilage and further, the results were validated with multiple reaction monitoring assay. RESULTS: In the healthy cartilage pairs, there was no significant variation in protein profiles between 2 adjacent sample sites. In pairs of tissue that contained a sample of GI/GII tissue, there were both significant microstructural changes as well as the difference in abundance levels of 24 proteins. CONCLUSIONS: From the known functions of the 24 proteins, found to be strongly aligned with the specific microstructural changes observed, a unique "proteins ensemble" involved in the initiation and progression of early cartilage degeneration is proposed.

Comparison of Human Articular Cartilage Tissue and Chondrocytes Isolated from Peripheral versus Central Regions of Traumatic Lesions.

OBJECTIVE: Cellular and molecular events occurring in cartilage regions close to injury are poorly investigated, but can possibly compromise the outcome of cell-based cartilage repair. In this study, key functional properties were assessed for cartilage biopsies collected from the central part of traumatic joint lesions (central) and from regions surrounding the defect (peripheral). These properties were then correlated with the quality of the initial cartilage biopsy and the inflammatory state of the joint. DESIGN: Cartilage samples were collected from knee joints of 42 patients with traumatic knee injuries and analyzed for cell phenotype (by reverse transcriptas-polymerase chain reaction), histological quality, cellularity, cell viability, proliferation capacity, and post-expansion chondrogenic capacity of chondrocytes (in pellet culture). Synovium was also harvested and analyzed for the expression of inflammatory cytokines. RESULTS: Cartilage quality and post-expansion chondrogenic capacity were higher in peripheral versus central samples. Differences between these 2 parameters were more pronounced in joints with high inflammatory features characterized by >100-fold difference in the mRNA levels of IL6 and IL8 in the corresponding synovium. Peripheral chondrocytes isolated from good- versus bad-quality biopsies expressed higher levels of collagen II/I and aggrecan/versican and lower levels of MMP13 and ADAMTS5. They also exhibited reduced proliferation and enhanced cartilage-forming capacity. CONCLUSIONS: Chondrocytes at the periphery of traumatic lesions better maintain properties of healthy cartilage compared to those isolated from the center, even when derived from bad-quality tissues harvested from highly inflamed joints. Future studies are necessary to investigate the change of functional properties of peripheral chondrocytes over time.

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

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