NADPH oxidase 4 deficiency attenuates experimental osteoarthritis in mice.

OBJECTIVE: Low-grade inflammation plays a pivotal role in osteoarthritis (OA) through exposure to reactive oxygen species (ROS). In chondrocytes, NADPH oxidase 4 (NOX4) is one of the major ROS producers. In this study, we evaluated the role of NOX4 on joint homoeostasis after destabilisation of the medial meniscus (DMM) in mice. METHODS: Experimental OA was simulated on cartilage explants using interleukin-1ß (IL-1ß) and induced by DMM in wild-type (WT) and NOX4 knockout (NOX4-/-) mice. We evaluated NOX4 expression, inflammation, cartilage metabolism and oxidative stress by immunohistochemistry. Bone phenotype was also determined by micro-CT and histomorphometry. RESULTS: Whole body NOX4 deletion attenuated experimental OA in mice, with a significant reduction of the OARSI score at 8 weeks. DMM increased total subchondral bone plate (SB.Th), epiphysial trabecular thicknesses (Tb.Th) and bone volume fraction (BV/TV) in both NOX4-/- and wild-type (WT) mice. Interestingly, DDM decreased total connectivity density (Conn.Dens) and increased medial BV/TV and Tb.Th only in WT mice. Ex vivo, NOX4 deficiency increased aggrecan (AGG) expression and decreased matrix metalloproteinase 13 (MMP13) and collagen type I (COL1) expression. IL-1ß increased NOX4 and 8-hydroxy-2'-deoxyguanosine (8-OHdG) expression in WT cartilage explants but not in NOX4-/-. In vivo, absence of NOX4 increased anabolism and decreased catabolism after DMM. Finally, NOX4 deletion decreased synovitis score, 8-OHdG and F4/80 staining following DMM. CONCLUSION: NOX4 deficiency restores cartilage homoeostasis, inhibits oxidative stress, inflammation and delays OA progression after DMM in mice. These findings suggest that NOX4 represent a potential target to counteract for OA treatment.

The effect of BMI on long-term outcomes after operatively treated ankle fractures: a study with up to 16 years of follow-up.

BACKGROUND: Ankle fractures are a common injury and the main cause of post-traumatic ankle arthritis. The prevalence of obesity is increasing worldwide, and this population is known to have poorer short and midterm outcomes after ankle fractures. Our objective is to assess long-term patient-reported outcomes in patients with operatively treated ankle fractures, and the effect of BMI on these results using the new and validated patient-reported outcome questionnaire, the Manchester Oxford foot and ankle questionnaire (MOXFQ). METHODS: We performed a retrospective review of all ankle fractures treated operatively in a ten-year period from 2002-2012. The MOXFQ and SF-12 were sent to all patients and were obtained, on average, 11.1 years after surgery (range 5.3-16.2 years). RESULTS: Two thousand fifty-five ankle fractures were reviewed, of which 478 (34%) patients completed the questionnaires. The mean age was 48.1 ± 15.5 years, 52% were men and the mean BMI was 26.1 ± 4.5 kg/m2. Of the 478, 47% were of normal weight, 36% were overweight, and 17% were obese. Overall, 2.1% were type A, 69.9% B, and 24.9% type C fractures. There were no significant differences in the type of fracture between the BMI groups. Comparing obese and non-obese patients, there were large differences in MOXFQ pain (33 ± 29 vs. 18.7 ± 22.1, effect size 0.55), and function scores (27.3 ± 29 vs. 12.5 ± 21.1, effect size 0.58). No differences in complications and reoperations rates were observed. The BMI value at surgery correlated more strongly with the MOXFQ pain score than the BMI at follow-up (Spearman's Rho 0.283 vs. 0.185, respectively). CONCLUSION: These findings reveal that obese patients have significant worse long-term outcomes, namely increased pain, poorer function, and greater impairment in everyday life after an operatively treated ankle fracture. Moreover, pain and function linearly declined with increasing BMI. Our findings appear to indicate that increased BMI at surgery is an important contributor to adverse outcome in the operative management of rotational ankle fractures. LEVEL OF EVIDENCE: III.

Human myoblasts differentiate in various mesenchymal lineages and inhibit allogeneic T cell proliferation through an indolamine 2,3 dioxygenase dependent pathway.

Muscle stem cells (MuSC) are considered as a reliable source of therapeutic cells to restore diseased muscles. However in most cases, injected MuSC-derived myoblasts are rapidly destroyed by the host immune response, which impairs the beneficial effect. By contrast, human mesenchymal stromal cells (MSC), have been reported to exhibit potent immune regulatory functions. Thus, we investigated, in vitro, the multipotent differentiation- and immunosuppressive capacities of human myoblasts and compared these features with those of human MSC. Myoblasts shared numerous cell surface markers with MSC, including CD73, CD90, CD105 and CD146. Both cell type were negative for HLA-DR and CD45, CD34 and CD31. CD56, a myogenic marker, was expressed by myoblasts exclusively. Myoblasts displayed multipotent potential capabilities with differentiation in chondrocytes, adipocytes and osteoblasts in vitro. Myoblasts also inhibited allogenic T cell proliferation in vitro in a dose dependent manner, very similarly to MSC. This effect was partly mediated via the activation of indolamine 2,3 dioxygenase enzyme (IDO) after IFNγ exposure. Altogether, these data demonstrate that human myoblasts can differentiate in various mesenchymal linages and exhibit powerful immunosuppressive properties in vitro. Such features may open new therapeutic strategies for MuSC-derived myoblasts.

Arthroscopic treatment of a lipoma arborescens of the elbow: A case report.

INTRODUCTION: Lipoma Arborescens is a rare pathology that mainly affects the knee. Occurrences in the elbow are even more uncommon and mainly involve the bicipitoradial bursa. CASE'S DESCRIPTION: We describe the case of a 54-year-old patient known for rheumatoid arthritis, who consulted for chronic elbow pain associated with swelling and limited extension. DIAGNOSIS: The diagnosis of a lipoma arborescens of the elbow involving the whole joint was made using magnetic resonance imaging and confirmed during arthroscopy. INTERVENTIONS: After a failed nonoperative treatment consisting in intra-articular cortisone injections and physiotherapy, the patient underwent arthroscopic synovectomy and arthrolysis. OUTCOME: At 1-year follow-up, he reported no pain, satisfactory range of motion, and major improvements in clinical scores. CONCLUSION: This is the first illustrated case report about lipoma arborescens involving the whole elbow joint. Even though it is a rare disease, awareness of its presentation, imaging patterns, and treatment options is therefore important for clinicians, radiologists, and surgeons. In this case, arthroscopic treatment resulted in satisfactory and long-lasting pain relief and functional results. It may be considered as a safe and effective option in case of failed nonoperative measures.

In vitro evaluation of human myoblast function after exposure to cobalt and chromium ions.

The replacement of a native hip joint by a metal-on-metal prosthesis may induce deleterious inflammatory side effects that are associated with the release of wear particles and metal ions. These events are referred to the adverse reaction to metal debris (ARMD) and the adverse local tissue reaction (ALTR). While wear particles seem involved in ARMD, the role of metal ions in ALTR and their impact on myoblasts, located in the prosthesis vicinity, has not been fully identified. To clarify this issue we investigated, using an in vitro culture system, the effect of cobalt and/or chromium ions (Co2+ and/or Cr3+ ) on human myoblast proliferation, cellular differentiation, and inflammatory marker expression. Freshly isolated human myoblasts were cultured in media supplemented with graded concentrations of Co2+ and/or Cr3+ . Co2+ induced a concentration-dependent decrease of both myoblast viability and myogenic differentiation while Cr3+ did not. Co2+ or Co2+ /Cr3+ also induced the upregulation of ICAM-1, whereas HLA-DR expression was unaffected. Moreover, allogenic monocytes induced the synergistic increase of Co2+ -induced ICAM-1 expression. We also found that Co2+ stabilized HIF-1α and increased TLR4, tumor necrosis factor-alpha (TNF-α), and interleukin 1ß (IL-1ß) expression in a dose and time-dependent manner in human myoblasts. This study showed that Co2+ , but not Cr3+ , was toxic toward myoblasts and induced, in the surviving cells, expression of inflammatory markers such as ICAM-1, TLR4, TNF-α, and IL-1ß. This suggests that Co2+ , most efficiently in the presence of monocytes, may be a key inducer of ALTR, which may, if severe and long-lasting, eventually result in prosthesis loosening.