Alain Sautet

Crucial Role of Visfatin/Pre-B Cell Colony-Enhancing Factor in Matrix Degradation and Prostaglandin E2 Synthesis in Chondrocytes : Possible Influence on Osteoarthritis

OBJECTIVE Prostaglandin E2 (PGE2) is one of the main catabolic factors involved in osteoarthritis (OA), and metalloproteinases (MMPs) are crucial for cartilage degradation. PGE2 synthesis under inflammatory conditions is catalyzed by cyclooxygenase 2 and microsomal PGE synthase 1 (mPGES-1), whereas NAD+-dependent 15-hydroxy-PG dehydrogenase (15-PGDH) is the key enzyme implicated in PGE2 catabolism. The present study was undertaken to investigate the contribution of visfatin, an adipose tissue-derived hormone, to the pathophysiology of OA, by examining its role in PGE2 synthesis and matrix degradation. METHODS The synthesis of visfatin by human chondrocytes from OA patients, with and without stimulation with interleukin-1beta (IL-1beta) and the role of visfatin in PGE2 synthesis were analyzed by real-time reverse transcriptase-polymerase chain reaction (RT-PCR) and immunoblotting. The effects of visfatin (1-10 microg/ml) on mPGES-1 and 15-PGDH synthesis, on the subsequent release of PGE2, and on MMP-3, MMP-13, ADAMTS-4, ADAMTS-5, and PG synthesis by primary immature mouse articular chondrocytes were examined by quantitative RT-PCR, immunoblotting, and enzyme-linked immunosorbent assay. Finally, small interfering RNA (siRNA) was used to assess the influence of visfatin on IL-1beta-induced release of PGE2 in immature mouse articular chondrocytes. RESULTS Human OA chondrocytes produced visfatin, and visfatin synthesis was increased by IL-1beta treatment. Visfatin, like IL-1beta, triggered excessive release of PGE2, due to increased mPGES-1 synthesis and decreased 15-PGDH synthesis. Visfatin knockout with siRNA reduced IL-1beta-induced PGE2 overrelease. Visfatin triggered ADAMTS-4 and ADAMTS-5 expression and MMP-3 and MMP-13 synthesis and release, and reduced synthesis of high molecular weight PG by immature mouse articular chondrocytes. CONCLUSION The findings of this study indicate that visfatin has a catabolic function in cartilage and may have an important role in the pathophysiology of OA.

Acromioclavicular dislocations: Treatment by coracoacromial ligamentoplasty

We did a retrospective review of 32 patients who had undergone acute treatment for acromioclavicular joint dislocation (mean follow-up period 46 months) and 24 patients who had undergone surgery for chronic joint dislocation (mean follow-up period 51 months). All patients had a ligamentoplasty performed using the coracoacromial ligament. With the shoulder functional score described by Patte, we obtained 81% satisfactory results for the patients who underwent acute treatment and 79% satisfactory results for those who underwent late treatment. Because results in both groups were similar, we now treat only the more severe form of acute dislocation with surgery. Delayed surgery is indicated in those patients who have an unsatisfactory result after functional treatment.

Rotator interval lesions and their relation to coracoid impingement syndrome

In the last 10 years we have found impingement of the coracoid process on the rotator interval in 12 patients (14 shoulders). Seven of these patients were women and 5 were men; the average patient age was 48.5 years. One patient had a calcified coracohumeral ligament, another patient had an anterior tear of a repaired deltoid flap, and a third had an aberrant pectoralis minor tendon inserted into the rotator interval. Eleven patients had a weak rotator interval, and in 4 cases the rotator interval had a small tear. We closed the rotator interval in all 12 patients. We also performed a coracoidoplasty in 5 of the patients. The condition of all shoulders improved clinically after operation; the average follow-up was 4.2 years. Three patients (4 shoulders) still had moderate pain, and 7 patients (9 shoulders) lacked strength. Internal rotation was the only shoulder movement that remained limited. Although impingement seemed obvious during surgery, experimental studies have reported contradictory findings.

Expression and function of visfatin (Nampt), an adipokine-enzyme involved in inflammatory pathways of osteoarthritis

IntroductionVisfatin is an adipokine that may be involved in intertissular joint communication in osteoarthritis (OA). With a homodimeric conformation, it exerts nicotinamide phosphoribosyltransferase (Nampt) enzymatic activity, essential for nicotinamide adenine dinucleotide biosynthesis. We examined the tissular origin and conformation of visfatin/Nampt in human OA joints and investigated the role of visfatin/Nampt in chondrocytes and osteoblasts by studying Nampt enzymatic activity.MethodsSynovium, cartilage and subchondral bone from human OA joints were used for protein extraction or incubated for 24 hours in serum-free media (conditioned media), and synovial fluid was obtained from OA patients. Visfatin/Nampt expression in tissular extracts and conditioned media was evaluated by western blot and enzyme-linked immunosorbent assay (ELISA), respectively. Nampt activity was assessed in OA synovium by colorimetric assay. Primary cultures of murine chondrocytes and osteoblasts were stimulated with visfatin/Nampt and pretreated or not with APO866, a pharmacologic inhibitor of Nampt activity. The effect on cytokines, chemokines, growth factors and hypertrophic markers expression was examined by quantitative reverse transcriptase polymerase chain reaction and/or ELISA.ResultsIn tissular explants, conditioned media and synovial fluid, visfatin/Nampt was found as a homodimer, corresponding to the enzymatically active conformation. All human OA joint tissues released visfatin/Nampt (synovium: 628 ± 106 ng/g tissue; subchondral bone: 195 ± 26 ng/g tissue; cartilage: 152 ± 46 ng/g tissue), with significantly higher level for synovium (P <0.0005). Nampt activity was identified ex vivo in synovium. In vitro, visfatin/Nampt significantly induced the expression of interleukin 6, keratinocyte chemoattractant and monocyte chemoattractant protein 1 in chondrocytes and osteoblasts. APO866 decreased the mRNA and protein levels of these pro-inflammatory cytokines in the two cell types (up to 94% and 63% inhibition, respectively). Levels of growth factors (vascular endothelial growth factor, transforming growth factor β) and hypertrophic genes were unchanged with treatment.ConclusionVisfatin/Nampt is released by all human OA tissues in a dimeric enzymatically active conformation and mostly by the synovium, which displays Nampt activity. The Nampt activity of visfatin is involved in chondrocyte and osteoblast activation, so targeting this enzymatic activity to disrupt joint tissue interactions may be novel in OA therapy.

Characterization of diabetic osteoarthritic cartilage and role of high glucose environment on chondrocyte activation: toward pathophysiological delineation of diabetes mellitus-related osteoarthritis

OBJECTIVE To examine the relationship between osteoarthritis (OA) and type 2 diabetes mellitus (DM). METHODS OA cartilage from DM and non-DM patients undergoing knee replacement were stimulated by IL-1β for 24 h and release of interleukin-6 (IL-6) and prostaglandin E2 (PGE2) was measured. Primary cultured murine chondrocytes were stimulated for 24 and 72 h with or without IL-1β (5 ng/mL) under normal-glucose (5.5 mM) or high-glucose (25 mM) conditions. The expression and release of pro-inflammatory mediators (IL-6, cyclooxygenase 2 [COX2]/PGE2) were analyzed by quantitative RT-PCR and ELISA/EIA. Glucose uptake was assessed with ((14)C)-2-deoxyglucose. Reactive oxygen species (ROS) and nitric oxide (NO) production were measured. To analyze the mechanism of IL-1β-induced inflammation, cells were pretreated or treated with inhibitors of glucose transport (cytochalasin B), the polyol pathway (epalrestat), mitochondrial oxidative stress (MitoTEMPO) or nitric oxide synthase (l-NAME). RESULTS With IL-1β stimulation, IL-6 and PGE2 release was greater in human DM than non-DM OA cartilage (2.7- and 3-fold, respectively) (P < 0.05). In vitro, with IL-1β stimulation, IL-6 and COX2 mRNA expression, IL-6 and PGE2 release, and ROS and NO production were greater under high-than normal-glucose conditions in cultured chondrocytes. IL-1β-increased IL-6 release was reduced with cytochalasin B, epalrestat, L-NAME or MitoTEMPO treatment (-45%, -62%, -38% and -40%, respectively). CONCLUSION OA cartilages from DM patients showed increased responsiveness to IL-1β-induced inflammation. Accordingly, high glucose enhanced IL-1β-induced inflammation in cultured chondrocytes via oxidative stress and the polyol pathway. High glucose and diabetes may thus participate in the increased inflammation in OA.

Comparison of fondaparinux with low molecular weight heparin for venous thromboembolism prevention in patients requiring rigid or semi‐rigid immobilization for isolated non‐surgical below‐knee injury

In several small studies, anticoagulant therapy reduced the incidence of venous thromboembolism (VTE) in patients with isolated lower‐limb injuries.

Difficultés du transfert d’information en vue d’un consentement éclairé: Étude expérimentale chez 21 patients

Purpose of the study Delivering information to the patient, an ethical obligation recognized for years, has recently become a legal obligation. Proof of information delivery has become the legal responsibility of the surgeon. We conducted a prospective study to evaluate the quality of information transfer by assessing patient comprehension of information delivered in an orthopedic surgery unit.PURPOSE OF THE STUDY Delivering information to the patient, an ethical obligation recognized for years, has recently become a legal obligation. Proof of information delivery has become the legal responsibility of the surgeon. We conducted a prospective study to evaluate the quality of information transfer by assessing patient comprehension of information delivered in an orthopedic surgery unit. MATERIAL AND METHODS All patients attending consultations before undergoing arthroscopic treatment for rotator cuff tendinopathy were enrolled in this study when the consultation was conducted in the presence of an observer. Two questionnaires, one for the patient and one for the surgeon, were used to collect given information about the pathological condition, the modalities of treatment, and the expected results of the treatment and its complications. RESULTS All 21 patients included in the study considered they had been well informed and that they had understood their pathological condition as well as the complications of the proposed treatment. However, agreement between their stated comprehension and the information delivered was poor, varying from 15 to 50%. Furthermore, 90% of the patients stated they had understood the potential complications of the surgical procedure, despite the fact that the consulting surgeons had not (generally) provided information on such complications. DISCUSSION There is a gap between what the surgeon says (or thinks he/she says) and what the patient understands. Potential biases in this study (non-unbiased observer) might explain this discordance which was probably related to the unequal relationship between the patient and the physician for any consultation. Therefore, the basis of informed consent cannot be found in the details concerning complications actually delivered to the patient. Surgeons must become aware that the patients understand very little of their explanations. This does not mean that the information should not be delivered but on the contrary that it must be. The important point is not necessarily the information content but rather the quality of the human relationship enabling information transfer.Resume Situe au cœur de l’ethique medicale, le devoir d’information concerne tout particulierement le chirurgien orthopediste, appele, de par sa discipline, a porter atteinte a l’integrite physique d’autrui pour des raisons purement fonctionnelles. Pour savoir si l’information etait correctement transmise au cours d’une consultation, nous avons realise une etude prospective sur l’information recue lors d’une consultation pour des lesions chroniques de la coiffe des rotateurs relevant d’un traitement arthroscopique pendant qu’un observateur assistait a la consultation. Au cours de notre etude, nous avons montre qu’il existait une difference importante entre l’information donnee par le medecin et l’information comprise et retenue par le patient. La concordance entre l’information donnee par le chirurgien et celle retenue par le patient variait de 15 a 50 %. Des lors, la validite du concept du consentement eclaire est mise en doute si l’information qui doit le preceder n’est pas accessible au patient. La question ethique qui se pose aux chirurgiens est de savoir comment rendre cette information accessible aux patients, non pas pour pouvoir se defendre aupres des tribunaux, mais pour donner aux patients tous les elements necessaires a la prise de decision finale.

The nuclear factor-erythroid 2-related factor/heme oxygenase-1 axis is critical for the inflammatory features of type 2 diabetes–associated osteoarthritis

Epidemiological findings support the hypothesis that type 2 diabetes mellitus (T2DM) is a risk factor for osteoarthritis (OA). Moreover, OA cartilage from patients with T2DM exhibits a greater response to inflammatory stress, but the molecular mechanism is unclear. To investigate whether the antioxidant defense system participates in this response, we examined here the expression of nuclear factor-erythroid 2-related factor (Nrf-2), a master antioxidant transcription factor, and of heme oxygenase-1 (HO-1), one of its main target genes, in OA cartilage from T2DM and non-T2DM patients as well as in murine chondrocytes exposed to high glucose (HG). Ex vivo experiments indicated that Nrf-2 and HO-1 expression is reduced in T2DM versus non-T2DM OA cartilage (0.57-fold Nrf-2 and 0.34-fold HO-1), and prostaglandin E2 (PGE2) release was increased in samples with low HO-1 expression. HG-exposed, IL-1β-stimulated chondrocytes had lower Nrf-2 levels in vitro, particularly in the nuclear fraction, than chondrocytes exposed to normal glucose (NG). Accordingly, HO-1 levels were also decreased (0.49-fold) in these cells. The HO-1 inducer cobalt protoporphyrin IX more efficiently attenuated PGE2 and IL-6 release in HG+IL-1β-treated cells than in NG+IL-1β-treated cells. Greater reductions in HO-1 expression and increase in PGE2/IL-6 production were observed in HG+IL-1β-stimulated chondrocytes from Nrf-2−/− mice than in chondrocytes from wild-type mice. We conclude that the Nrf-2/HO-1 axis is a critical pathway in the hyperglucidic-mediated dysregulation of chondrocytes. Impairments in this antioxidant system may explain the greater inflammatory responsiveness of OA cartilage from T2DM patients and may inform treatments of such patients.

Cardiometabolic risk factors in primary centred and rotator cuff-related shoulder osteoarthritis: a comparative study

Background Risk factors for shoulder osteoarthritis (SOA) have been poorly studied. SOA has two anatomical subtypes: primary centred SOA (centred SOA) and rotator cuff-related OA (non-centred SOA). We examined whether cardiometabolic risk factors are preferentially associated with centred than mechanical-induced non-centred SOA. Methods This 2004–2012 retrospective multicentric study included patients with SOA. Data on clinical characteristics, especially cardiometabolic risk factors, were collected. We compared patients with radiographic-centred and non-centred SOA and tested the association between cardiometabolic risk factors and subtypes of SOA. Results We included 147 patients (101 women (68.7%); mean age 75.8±10 years); 99 had centred SOA. As compared with patients with non-centred SOA, those with centred SOA were older (77.5±9 vs 72.4±11 years; p=0.004) with no difference in cardiometabolic disturbances or their accumulation. Multivariable analyses indicated that older age was independently associated with centred SOA (OR 1.06;95% CI 1.02 to 1.1; p=0.004), and cardiovascular diseases were less associated with this subtype (OR 0.27; 95% CI 0.089 to 0.824; p=0.02) than with the non-centred one. Conclusion Cardiometabolic risk factors were not more prevalent with primary centred than rotator cuff-related SOA. They may participate in the pathophysiology of both SOA subtypes through cartilage and tendon disruption.

Balloon humeroplasty reconstruction for acute Hill-Sachs injury: A technical note

Posterior Hill-Sachs humeral defects are present in 80% to 100% of cases of anterior shoulder dislocation and are a factor in recurrent instability. Several techniques have been described to fill the defect and avoid recurrence. We developed a percutaneous technique to fill the newly created defect in which a percutaneous balloon, analogous to the one used in vertebral kyphoplasty, is used to reduce the defect, which is then filled with calcium phosphate cement. One patient with an acute anterior dislocation of the shoulder with no previous history was treated using this method. Early imaging results showed adequate reduction of the defect and no cement resorption. The patient was followed for 12 months; he had normal function of the shoulder and no recurrent dislocation. Shoulder computed tomography (CT) arthrography with contrast after 3 months showed an intact capsule and no recurrence of the defect. While this technique is certainly in its infancy, we have demonstrated that emergency reduction of the defect in acute first occurrence anterior shoulder dislocation is feasible, helps to restore normal anatomy of the humeral head and leads to good clinical results. Whether it can improve clinical results and prevent recurrent shoulder dislocation remains to be evaluated.