Cartilage collagen structure upon knee joint distraction and high tibial osteotomy as measured with T2-mapping MRI - post-hoc analyses of two RCTs

Objective High tibial osteotomy (HTO) and knee joint distraction (KJD) are joint-preserving treatments for knee osteoarthritis (OA) that have shown good clinical results and cartilage thickness increase. In this exploratory study, cartilage T2 relaxation times, as a measure of collagen structure, are evaluated after both treatments, and compared to natural OA progression. Design Ten patients indicated for total knee arthroplasty (TKA) were treated with KJD (KJDTKA). Thirty patients indicated for HTO were treated with KJD (KJDHTO; n = 10) or HTO (n = 20). 3T T2-mapping MRI scans were performed before and one (KJD groups only) and two years after treatment, from which cartilage was segmented and the volume and T2 relaxation times were calculated. Patients were matched with untreated patients from the Osteoarthritis Initiative (OAI) to compare the change in T2 values over time. Results KJDHTO (n = 8) and HTO (n = 17) patients both showed statistically significant increases in T2 values (worsening) but no volume changes. KJDTKA patients (n = 8) only showed a tendency for (first-year) T2 value increase, and a significant volume increase in the most affected compartment (MAC). There were no significant differences between the three groups. All treated patients combined showed a significantly higher increase in T2 times than untreated patients from the OAI for both femur and tibia. Conclusions KJD and HTO cause an increase in cartilage T2 relaxation times, which could indicate loss or reorganization of collagen structure integrity. In TKA-indicated KJD patients, this goes paired with volume increase, indicating it may be the result of maturation of newly formed cartilage

Human C-reactive protein aggravates osteoarthritis development in mice on a high-fat diet

Objective: C-reactive protein (CRP) levels can be elevated in osteoarthritis (OA) patients. In addition to indicating systemic inflammation, it is suggested that CRP itself can play a role in OA development. Obesity and metabolic syndrome are important risk factors for OA and also induce elevated CRP levels. Here we evaluated in a human CRP (hCRP)-transgenic mouse model whether CRP itself contributes to the development of ‘metabolic’ OA.Design: Metabolic OA was induced by feeding 12-week-old hCRP-transgenic males (hCRP-tg, n = 30) and wild-type littermates (n = 15) a 45 kcal% high-fat diet (HFD) for 38 weeks. Cartilage degradation, osteophytes and synovitis were graded on Safranin O-stained histological knee joint sections. Inflammatory status was assessed by plasma lipid profiling, flow cytometric analyses of blood immune cell populations and immunohistochemical staining of synovial macrophage subsets.Results: Male hCRP-tg mice showed aggravated OA severity and increased osteophytosis compared with their wild-type littermates. Both classical and non-classical monocytes showed increased expression of CCR2 and CD86 in hCRP-tg males. HFD-induced effects were evident for nearly all lipids measured and indicated a similar low-grade systemic inflammation for both genotypes. Synovitis scores and synovial macrophage subsets were similar in the two groups.Conclusions: Human CRP expression in a background of HFD-induced metabolic dysfunction resulted in the aggravation of OA through increased cartilage degeneration and osteophytosis. Increased recruitment of classical and non-classical monocytes might be a mechanism of action through which CRP is involved in aggravating this process. These findings suggest interventions selectively directed against CRP activity could ameliorate metabolic OA development

Can gait patterns be explained by joint structure in people with and without radiographic knee osteoarthritis?: Data from the IMI-APPROACH cohort

Objective To determine the association between joint structure and gait in patients with knee osteoarthritis (OA). Methods IMI-APPROACH recruited 297 clinical knee OA patients. Gait data was collected (GaitSmart®) and OA-related joint measures determined from knee radiographs (KIDA) and MRIs (qMRI/MOAKS). Patients were divided into those with/without radiographic OA (ROA). Principal component analyses (PCA) were performed on gait parameters; linear regression models were used to evaluate whether image-based structural and demographic parameters were associated with gait principal components. Results Two hundred seventy-one patients (age median 68.0, BMI 27.0, 77% female) could be analyzed; 149 (55%) had ROA. PCA identifed two components: upper leg (primarily walking speed, stride duration, hip range of motion [ROM], thigh ROM) and lower leg (calf ROM, knee ROM in swing and stance phases). Increased age, BMI, and radiographic subchondral bone density (sclerosis), decreased radiographic varus angle deviation, and female sex were statistically signifcantly associated with worse lower leg gait (i.e. reduced ROM) in patients without ROA (R2=0.24); in ROA patients, increased BMI, radiographic osteophytes, MRI meniscal extrusion and female sex showed signifcantly worse lower leg gait (R2=0.18). Higher BMI was signifcantly associated with reduced upper leg function for non-ROA patients (R2=0.05); ROA patients with male sex, higher BMI and less MRI synovitis showed signifcantly worse upper leg gait (R2=0.12). Conclusion Structural OA pathology was signifcantly associated with gait in patients with clinical knee OA, though BMI may be more important. While associations were not strong, these results provide a signifcant association between OA symptoms (gait) and joint structure.Pathophysiology and treatment of rheumatic disease

The catabolic-to-anabolic shift seen in the canine osteoarthritic cartilage treated with knee joint distraction occurs after the distraction period

Background Cartilage regenerative mechanisms initiated by knee joint distraction (KJD) remain elusive. Animal experiments that are representative for the human osteoarthritic situation and investigate the effects of KJD at consecutive time points could be helpful in this respect but are lacking. This study investigated the effects of KJD on the osteoarthritic joint of dogs on two consecutive timepoints. Methods Osteoarthritis was bilaterally induced for 10 weeks in 12 dogs using the groove model. Subsequently, KJD was applied to the right hindlimb for 8 weeks. The cartilage, subchondral bone and synovial membrane were investigated directly after KJD treatment, and after 10 weeks of follow-up after KJD treatment. Macroscopic and microscopic joint tissue alterations were investigated using the OARSI grading system. Additionally, proteoglycan content and synthesis of the cartilage were assessed biochemically. RT-qPCR analysis was used to explore involved signaling pathways. Results Directly after KJD proteoglycan and collagen type II content were reduced accompanied by decreased proteoglycan synthesis. After 10 weeks of follow-up, proteoglycan and collagen type II content were partly restored and proteoglycan synthesis increased. RT-qPCR analysis of the cartilage suggests involvement of the TGF-β and Notch signalling pathways. Additionally, increased subchondral bone remodelling was found at 10 weeks of follow-up. Conclusion While the catabolic environment in the cartilage is still present directly after KJD, at 10 weeks of follow-up a switch towards a more anabolic joint environment was observed. Further investigation of this timepoint and the pathways involved might elucidate the regenerative mechanisms behind KJD. The Translational Potential of this Article Further elucidation of the regenerative mechanisms behind KJD could improve the existing KJD treatment. Furthermore, these findings could provide input for the discovery or improvement of other joint regenerative treatment strategies

Selective COX-2 inhibition is favorable to human early and late-stage osteoarthritic cartilage: a human in vitro study

SummaryObjectiveNonsteroidal anti-inflammatory drugs (NSAIDs) are widely used in the treatment of osteoarthritis (OA). For the outcome of treatment the direct effects of NSAIDs on cartilage may be more important than indirect effects on inflammation, considered being secondary in OA. For clinical practice, it is relevant to study effects of NSAIDs on early stages of OA. Therefore we studied the direct effects of celecoxib on human degenerated OA cartilage and compared the effects with those on human healthy cartilage and human end-stage OA cartilage.MethodsDegenerated, late-stage OA, and healthy human articular cartilage were exposed (7 days of culture) to celecoxib (0.1–10μM). Changes in cartilage proteoglycan turnover (synthesis, retention, and release), proteoglycan content, prostaglandin E2 (PGE2) and nitric oxide (NO) production were determined.ResultsBoth degenerated and established OA cartilage showed its characteristic changes in proteoglycan turnover (all P<0.05). Celecoxib at 1μM was able to increase synthesis of degenerated cartilage and normalize both releases of newly formed and resident proteoglycans. Importantly, 1μM celecoxib influenced matrix integrity by enhancing proteoglycan content. Similar results were found for end-stage OA cartilage. Enhanced PGE2 production in degenerative and OA cartilage could be decreased by celecoxib, whereas no effect on enhanced NO production was found. No significant effects of celecoxib on normal cartilage were found.DiscussionCelecoxib, in a clinical relevant concentration, showed in vitro a significant beneficial effect, not only on late-stage OA but also on more early stages of OA, whereas healthy cartilage remained unaffected, suggesting chondroprotective properties of celecoxib in the treatment of degenerative joint disorders