Pathological Fracture of the Proximal Humerus Occurred on Metastases of Probable Kidney Origin in the Absence of Primary Lesions: A Case Report.

Cancer of unknown primary (CUP) origin represents a diagnostic and therapeutic challenge. These tumours spread to different parts of the body even if the site of origin has not been identified. When renal metastases are observed without an obvious primary lesion, it is important to exclude the possibility of a primary kidney tumour that may be unknown or too small to be detected. The diagnosis of CUP is established after a careful clinical evaluation and diagnostic tests, including blood chemistry and laboratory tests, instrumental exams (CT, MRI, PET, bone scan), biopsy, and molecular and cytogenetic analysis. Once the diagnosis of CUP with kidney metastases is confirmed, treatment depends on the location of the metastases, the patient's health status, and available treatment options. The latter includes surgery to remove metastases, radiation therapy, or systemic treatment such as chemotherapy or immunotherapy. It is important that patients with CUP are evaluated by a multidisciplinary team of specialists, who can contribute to planning the most appropriate treatment. In this article, we report the clinical case of a patient with a pathological fracture of the proximal humerus which occurred on metastases of probable renal origin in the absence of primary lesions.

Spinal cord injuries in the absence of post-traumatic radiographic anomalies (SCIWORA): the traumatic moment between patient anterior state and efficient/concurrent causes of injury.

BACKGROUND AND AIM: Spinal Cord Injury without Radiographic Abnormality (SCIWORA) represents acute traumatic myelopathy in the absence of instrumental evidence of fractures and/or dislocations of the cervical vertebrae. METHODS: In this article we present 4 cases of SCIWORA that came to our observation and the medico-legal implications associated with them. RESULTS: In defining the compensation in the context of a private accident policy for traumatic pathologies of the spinal cord, an in-depth medical-legal assessment is essential, based on an accurate examination of the health documentation including the instrumental investigations performed, the anamnesis and an accurate evaluation of the trauma dynamic. The paraphysiological deterioration of organ-tissue structures, identifiable in the concept of "natural variability of biological risk", should be included in the same definition of insured risk by age group, with the consequence that physical conditions that fall within the physiological or paraphysiological definitions, although potentially contributing to injury, do not necessarily exclude compensation. A different concept dominates the variability of the compensation according to a paraphysiological pre-existing condition. The two arguments therefore call for thorough consideration of both the paraphysiological contributing causes of injury and/or impairment as necessarily subject to a preliminary study, which through the clinical and instrumental investigation method, will define the perimeter of functionality.

Refractory humeral non-union: treatment with photodynamic intramedullary implant IlluminOss® and internal fixation.

Surgically treated humeral shaft fractures can develop into pseudoarthrosis (PSA). Even if PSA is treated according to the proposed literature, refractory non-union of the humerus can be determined. Due to the rarity of this condition, we report our experience in the management of refractory pseudarthrosis of the humerus at the IRCCS Galeazzi Orthopedic Institute (Milan, Italy). We used internal fixation with plate and screws associated with the implant of the IlluminOss® Photodynamic Bone Stabilization System to increase bone stability and improve anchoring of the implant medium. This combined treatment allowed the consolidation of the complex fracture despite the bone loss, ensuring excellent stability of the fracture stumps and constituting a flexible and stable system with the most favourable biomechanical conditions. An increase in refractory PSA cases is likely in the future, due to a higher incidence of surgically treated humeral shaft fractures than in the past. Further studies on the effectiveness of the combined use of plate and screw and the IlluminOss® system will be indispensable.

Treatment of Femoral Shaft Pseudarthrosis, Case Series and Medico-Legal Implications.

Pseudarthrosis (PSA) is a possible complication of femoral shaft fracture treatment. It is often associated with reduced bone quality and can, therefore, adversely affect quality of life. Its treatment poses a major challenge for orthopaedic surgeons. Several authors have set forth different surgical approaches for the treatment of pseudarthrosis, such as internal fixation with plate and screws, replacement of an intramedullary nail or prosthetic replacement. In cases associated with bone loss, osteopenia, or comminution of fracture fragments, autologous or homologous bone grafts may also be used. The chronic outcomes of the surgical treatment of femoral shaft pseudarthrosis, even when consolidation is achieved, are linked to disabling sequelae of clinical-functional relevance, deserving an adequate medico-legal evaluation. The purpose of this retrospective study is to analyse a clinical case series of patients treated for atrophic femoral shaft pseudarthrosis at the IRCCS Orthopaedic Institute Galeazzi, Milan, Italy, from 2014 to 2020 and their orthopaedic-traumatological and medico-legal implications.

How the COVID-19 Pandemic Affected Attendance at a Tertiary Orthopedic Center Emergency Department: A Comparison between the First and Second Waves.

Italy was the first European country to face the SARS-CoV-2 virus (COVID-19) pandemic in 2020. The country quickly implemented strategies to contain contagions and re-organize medical resources. We evaluated the COVID-19 effects on the activity of a tertiary-level orthopedic emergency department (ED) during the first and second pandemic waves. We retrospectively collected and compared clinical radiological data of ED admissions during four periods: period A, first pandemic wave; period B, second pandemic wave; period C, three months before the COVID-19 outbreak; period D, same timeframe of the first wave but in 2019. During period A, we found a reduction in ED admissions (-68.2% and -59.9% compared with periods D and C) and a decrease in white codes (non-urgent) (-7.5%) compared with pre-pandemic periods, with a slight increase for all other codes: +6.3% green (urgent, not critical), +0.8% yellow (moderately critical) and +0.3% red (highly urgent, risk of death). We observed an increased rate of fracture diagnosis in period A: +14.9% and +13.3% compared with periods D and C. Our study shows that the COVID-19 pandemic caused a drastic change in the ED patient flow and clinical radiological activity, with a marked reduction in admissions and an increased rate of more severe triage codes and diagnosed fractures.

A case of critical ischemia of the lower limbs: critical elements and possible medico-legal implications.

Peripheral arterial disease (PAD) is an atherosclerotic process that causes stenosis and occlusion of non-cerebral and non-coronary arteries. Critical ischemia of the lower limbs is the most advanced and severe state of arterial disease. The purpose of this work is to underline the importance of a timely diagnostic-therapeutic framework in case of critical ischemia of the lower limbs, through a precise, coordinated, and multidisciplinary teamwork. A significant example is represented by the presentation of a clinical case that came to our observation following a request for compensation and which required an adequate evaluation in the medical-legal field. This work will make possible to clarify any profiles of medical professional responsibility, with specific reference to the predictability and preventability of the unfavorable events that have occurred, and which have led to a progressive worsening of the patient's clinical condition, which then resulted in the amputation of the lower limb, associated to organic deterioration and progressive complete permanent disability. In these cases, the collection of semeiological data must be careful, meticulous, and completed by suitable instrumental investigations. These data, with the exhaustive compilation of the medical record, play a decisive role even in the presence of adverse events and/or infrequent complications, in order to demonstrate from a medico-legal point of view that despite the implementation of all precautions codified by the specialized discipline, the adverse event, however foreseeable, is not always concretely preventable and therefore avoidable, being included in the non-negligent "complication" and not necessarily attributable to professional responsibility.

Brachial plexus paralysis in a patient with clavicular fracture, medico-legal implications.

Clavicular fractures make up 2.6-4% of all fractures in adults. The most frequent mechanism of injury is a fall with direct trauma to the shoulder during sports or road accidents. These fractures can have acute complications such as vascular lesions, nerve injuries, pneumothorax, and musculoskeletal injury. Primary brachial plexus injuries are rare events, both in the adult and paediatric population, have an incidence of less than 1% and are usually caused by direct compression of the fragments. We describe a case of midshaft clavicular fracture treated conservatively with a figure-eight bandage, associated with acute brachial plexus injury, and possible medico-legal repercussions thereof. It is important to recognize the progression of neurological deficits early on, in order for appropriate treatment to be undertaken promptly. Patients must be monitored and re-evaluated within few days after the injury to check the correct positioning of the brace, its degree of tolerability, and the possible onset of neurological deficits, because some clavicular fractures can be associated with compression of the brachial plexus.

Traumatology: Adoption of the Sm@rtEven Application for the Remote Evaluation of Patients and Possible Medico-Legal Implications.

Telemedicine is the combination of technologies and activities that offer new remote ways of medical care. The Sm@rtEven application project is a remote assistance service that follows patients affected by lower limb fractures surgically treated at Galeazzi Orthopedic Institute (Milan, Italy). The Sm@rtEven application aims to evaluate the clinical conditions of patients treated for lower limb fracture after discharge from hospital using remote follow-up (FU). The project is not a substitute for traditional clinical consultations but an additional tool for a more complete and prolonged view over time. The Sm@rtEven application is installed on patients' smartphones and is used daily to communicate with healthcare personnel. In the first protocol, patients had to complete different tasks for 30 days, such as monitoring the load progression on the affected limb, the number of steps during the day, and body temperature and completing a questionnaire. A simplified protocol was proposed due to the pandemic and logistical issues. The revised protocol enrolled patients after more than 30 days of their operation, prioritized the rehabilitation phase, and required patients to use the app for fewer days. After an initial phase of correct use, a reduction in patient compliance was gradually reported in the first protocol. However, patient compliance in the second protocol remained high (96.25%) in the recording of all the required parameters. The Sm@rtEven application has proven to be a valuable tool for following patients remotely, especially during the pandemic. Telemedicine has the same value as traditional clinical evaluations, and it enables patients to be followed over long distances and over time, minimizing any discomfort.

Atrophic pseudarthrosis of humeral diaphyseal fractures: medico-legal implications and methodological analysis of the evaluation.

Humeral shaft fractures account for 1- 3% of all fractures and about 20-27% of those involving the humerus. In the past they were often conservatively treated, with an acceptable consolidation rate. Open reduction and internal fixation (ORIF) is the best choice in polytrauma patients, in complex or pathological fractures and in those associated with vascular injuries. Regardless the type of fixation used, these fractures can evolve into delayed union or pseudarthrosis (PSA). It should be noted that the humeral shaft itself has a high intrinsic healing potential, due to the blood supply provided by the surrounding muscles. The aim of this work is to evaluate whether the causes that led to the development of atrophic pseudarthrosis in a humeral diaphyseal fracture are attributable to inadequate management of this fearful complication and to highlight the possible medico-legal repercussions. We will try to verify whether the currently used forensic evaluation parameters of permanent disability are appropriate and adequate in relation to the complexity of such injuries. This complexity also includes the repercussions on the ergonomic efficiency of the entire limb, the relative possible postural alterations, the inevitable extension of the period of traumatic illness and the relative repercussions on the overall compromised structure of the subject.

COVID-19 Elderly Patients Treated for Proximal Femoral Fractures during the Second Wave of Pandemic in Italy and Iran: A Comparison between Two Countries.

Background and objevtive: The worldwide spread of SARS-CoV-2 has affected the various regions of the world differently. Italy and Iran have experienced a different adaptation to coexistence with the pandemic. Above all, fractures of the femur represent a large part of the necessary care for elderly patients. The aim of this study was to compare the treatment in Italy and Iran of COVID-19-positive patients suffering from proximal femur fractures in terms of characteristics, comorbidities, outcomes and complications. Materials and Methods: Medical records of COVID-19-positive patients with proximal femoral fractures treated at IRCCS Istituto Ortopedico Galeazzi in Milan (Italy) and at Salamat Farda and Parsa hospitals in the province of Tehran (Iran), in the time frame from 1 October 2020 to 16 January 2021, were analyzed and compared. Results: Records from 37 Italian patients and 33 Iranian patients were analyzed. The Italian group (mean age: 83.89 ± 1.60 years) was statistically older than the Iranian group (mean age: 75.18 ± 1.62 years) (p value = 0.0003). The mean number of transfusions for each patient in Italy was higher than the Iranian mean number (p value = 0.0062). The length of hospital stay in Italy was longer than in Iran (p value < 0.0001). Furthermore, laboratory values were different in the post-operative value of WBC and admission and post-operative values of CRP. Conclusions: The present study shows that differences were found between COVID-19-positive patients with proximal femoral fractures in these two countries. Further studies are required to validate these results and to better explain the reasons behind these differences.

The epidemiology of proximal femur fractures during COVID-19 emergency in Italy: a multicentric study.

BACKGROUND AND AIM: After the first Italian case of Covid-19, the Government imposed the complete closure of all areas involved by the spread of the virus to contain transmissions. There was a massive reorganization of Hospitals, a stop of all elective activities and a convertion of many hospitals in "Covid Centers''. AITOG (Associazione Italiana Traumatologia e Ortopedia Geriatrica) conducted a retrospective study on all proximal femur fractures surgeries that occurred in this period, to find out whether the pandemic and the correlated lockdown somehow changed the incidence of these events.  Methods: 10 Italian orthopedic centers were involved in the study. Considering the geographic location, three groups were created (North, Centre and South). The considered period is the Italian "Phase 1" (February 23rd - May 3rd 2020). RESULTS: the cohort is composed of 412 patients, 116 male and 296 female (mean age 81.1 ± 9.1 years). The same period of 2019 has been used as control group, with 558 patients, 156 male and 402 female (mean age 84.2 ± 8.0 years). In 2020 we counted 323 (78.4%) fractures occurred at home, 61 (14.8%) in retirement houses and 28 (6.8%) in different locations. We mainly treated fractures with intramedullary nails (n.237 57.5%). Among all patients we had 46 (11.1%) Covid-19 positive. The mortality rate within 30 days was of 51 patients (12.4%); 23 of these died because of complications related to Covid-19 while 31 of  these were in treatment with anticoagulant/antiaggregant. CONCLUSIONS: AITOG analysis demonstrates a decrease in surgical interventions for proximal femur fractures from 2019 to 2020, a reduction in patients mean age and an increase in trauma occurred in domestic environment. We also registered a consistent difference between the North, Center and South of the Country.

Effect of the COVID-19 Outbreak on Pediatric Patients' Admissions to the Emergency Department in an Italian Orthopedic Trauma Hub.

BACKGROUND: The rapid diffusion of Coronavirus disease (COVID-19) in Northern Italy led the Italian government to dictate a national lockdown from 12 March 2020 to 5 May 2020. The aim of this observational cohort study is to analyze the differences in the number of pediatric patients' admission to the Emergency Room (ER) and in the type and causes of injury. METHODS: The pediatric population during the pandemic was compared to a similar group of patients admitted to the ER in 2019. Sex, age, triage color-code at admission, cause of trauma and presence of symptoms related to COVID-19 infection, discharge diagnosis and discharge modes were investigated. RESULTS: The lockdown period led to a reduction of 87.0% in ER admissions with a particular decrease in patients older than 12 years old. Moreover, a trend towards more severe codes and an increase in home-related injuries were observed during the pandemic, whereas the diagnosis of fracture was less frequent in the pre-pandemic group (p < 0.0001). CONCLUSIONS: A significant decrease in the ER attendances was reported during the lockdown. A shift in the cause and type of injury was observed; only the most serious traumas sought medical care with a higher percentage of severe triage codes and fractures.

How SARS-CoV-2 Pandemic Changed Traumatology and Hospital Setting: An Analysis of 498 Fractured Patients.

BACKGROUND: SARS-CoV-2 pandemic is one of the biggest challenges for many health systems in the world, making lots of them overwhelmed by the enormous pressure to manage patients. We reported our Institutional Experience, with specific aims to describe the distribution and type of treated injuries, and the organizational setup of our hospital. METHODS: Data of fractured patients admitted for surgical treatment in the time frames 9 March 2020-4 May 2020 and 1 March 2019-31 May 2019 were collected and compared. Furthermore, surgery duration and some parameters of effectiveness in health management were compared. RESULTS: A total of 498 patients were included. Mean age significantly lower age in 2019 and femoral fractures were significantly more frequent 2020. Mean surgery time was significantly longer in 2020. Mortality rate difference between the two years was found to be statistically significant. Time interval between diagnosis and surgery and between diagnosis and discharge/decease was significantly lower in 2020. In 2020, no patient admitted with a negative swab turned positive in any of the following tests for SARS-CoV-2. CONCLUSIONS: The COVID-19 pandemic has modified the epidemiology of hospitalized patients for traumatic reasons, leading to an increased admission of older patients with femoral fractures. Nevertheless, our institutional experience showed that an efficient change in the hospital organization, with an improvement of several parameters of effectiveness in health management, led to a null infection rate between patients.

From Standard to Escalated Anticoagulant Prophylaxis in Fractured Older Adults With SARS-CoV-2 Undergoing Accelerated Orthopedic Surgery.

Proximal femoral fractures in older adults are not uncommon and represent a great challenge for orthopedic surgeons because of the high risks of complications. In the COVID-19 panorama, fractures occurring in infected older adults become an even more intricate task because of concomitant metabolic derangements due to SARS-CoV-2. Multidisciplinary protocols are mandatory and pharmacological treatment in infected patients should be tailored. Regrettably, the spread of the virus in northern Italy, has been faster than scientific progress in characterizing the disease and many hospitals have had to manage the symptoms on a daily clinical bases. Our Italian hospital in the region of Lombardy, which has been the epicenter of the Italian pandemic, has admitted sixteen patients with fractured femurs in March and April 2020. The first seven patients were treated with the antithrombotic prophylaxis of a single daily dose of low-molecular-weight heparin, but we observed the highest prevalence of deaths from cardiovascular complications (four deaths). By doubling the daily dose of anticoagulants in the subsequent patients, we observed a reduction in the incidence of death (one death out of nine). Controversies exist about the surgical treatment of fractures in older adults during this pandemic. However, we have observed an increased survival after fall trauma in infected older adults if treated with high doses of anticoagulant. Although not being statistically significant, our results are in line with the current knowledge of the pathophysiology of SARS-CoV-2 infection, but more studies should be shared about the efficacy and dosage of anticoagulants in traumatic injuries of the elderly.

Changes of clinical activities in an orthopaedic institute in North Italy during the spread of COVID-19 pandemic: a seven-week observational analysis.

PURPOSE: The COVID-19 pandemic is importantly affecting the orthopaedic practice all over the world with Northern Italy being the first European area that faced the worst scenario. In this study, the changes in clinical practice occurred in an orthopaedic center in Milan are described. METHODS: Number and type of admissions, outpatients cancelled and preserved, emergency room, and intensive care unit activities have been analyzed in the timeframe of seven weeks since the beginning of the pandemic (from February 24th to April 10th) and compared with the same period in 2019. RESULTS: The planned surgical admissions declined from 2172 in 2019 to 664 in 2020 (69.42%, p < 0.0001), while emergencies increased from 158 to 268 (69.62%). The rehabilitation admissions declined from 414 to 69 (83.33%). The overall admission decreased by 63.52%, the trend showed a drop in the last weeks. Surgery performed in the COVID-19 operating room increased by 16.7% in the last week. Seven deaths occurred (0.7% of all orthopaedics and trauma admissions) compared with four (0.1%) which happened in the same period in 2019 (p = 0.004). Six of these patients were suffering from COVID-19. A total of 23,580 outpatients (93.8%) were cancelled. Emergency room consultations declined by 68.14% and 63.47% among white and green priority, respectively, while increased by 25% and 100% among yellow and red, respectively. CONCLUSION: These numbers show the radical changed scenario in an orthopaedic center in Milan during COVID-19 pandemic. Elective surgery declined rapidly going close to zero, outpatient admissions were restricted to cases that cannot be postponed, while emergencies increased due to the role played by the hospital as referral orthopaedic centre during the pandemic. The still ongoing emergency will have important impacts on the overall orthopaedic healthcare management for the next months.

Differences between orthopaedic evaluation and radiological reports of conventional radiographs in patients with minor trauma admitted to the emergency department.

INTRODUCTION: During night and on weekends, in our emergency department there is no radiologist on duty or on call: thus, X-ray examinations (XR) are evaluated by the orthopaedic surgeon on duty and reported the following morning/monday by radiologists. The aim of our study was to examine the discrepancy rate between orthopaedists and radiologists in the interpretation of imaging examinations performed on patients in our tertiary level orthopaedic institution and the consequences of delayed diagnosis in terms of patient management and therapeutic strategy. MATERIALS AND METHODS: We retrospectively reviewed all cases of discrepancy between orthopaedists and radiologists, which were categorized according to anatomical location of injury, initial diagnosis and treatment, change in diagnosis and treatment. We used the Chi square test to compare the frequencies of discrepancies between patients ≤14 and >14years of age. RESULTS: From January to December 2016, 19,512 patients admitted to our emergency department performed at least an imaging examination; among these patients, 13,561 underwent XR in absence of an attending radiologist. A discrepant diagnosis was found in 337/13,561 (2.5%; 184 males; mean age: 36.7±23.7, range 2-95); 151/337 (45%) discrepancies were encountered in the lower limbs, with ankle being the most common site of misdiagnosis (64/151), and 103/337 (30%) in the upper limbs, with the elbow being the most frequent site in this district (35/103). We found 293/337 false negatives (87%) and 44/337 false positives (13%), with 134 and 13 patients needing treatment change, respectively. We found 85/337 discrepancies (25%) in patients ≤14 years of age, and 252/337 (75%) in those >14years. The distribution of discrepancies per anatomic district was significantly different (P<0.001) in these two groups of patients. CONCLUSIONS: A low rate of discrepancy between orthopaedists and radiologists in evaluating images of patients admitted to our emergency department was found, although treatment change occurred in about half of cases. A thorough and accurate clinical evaluation is crucial to provide a correct treatment and prognosis.

Modeling Staphylococcus epidermidis-Induced Non-Unions: Subclinical and Clinical Evidence in Rats.

S. epidermidis is one of the leading causes of orthopaedic infections associated with biofilm formation on implant devices. Open fractures are at risk of S. epidermidis transcutaneous contamination leading to higher non-union development compared to closed fractures. Although the role of infection in delaying fracture healing is well recognized, no in vivo models investigated the impact of subclinical low-grade infections on bone repair and non-union. We hypothesized that the non-union rate is directly related to the load of this commonly retrieved pathogen and that a low-grade contamination delays the fracture healing without clinically detectable infection. Rat femurs were osteotomized and stabilized with plates. Fractures were infected with a characterized clinical-derived methicillin-resistant S. epidermidis (10(3), 10(5), 10(8) colony forming units) and compared to uninfected controls. After 56 days, bone healing and osteomyelitis were clinically assessed and further evaluated by micro-CT, microbiological and histological analyses. The biofilm formation was visualized by scanning electron microscopy. The control group showed no signs of infection and a complete bone healing. The 10(3) group displayed variable response to infection with a 67% of altered bone healing and positive bacterial cultures, despite no clinical signs of infection present. The 10(5) and 10(8) groups showed severe signs of osteomyelitis and a non-union rate of 83-100%, respectively. The cortical bone reaction related to the periosteal elevation in the control group and the metal scattering detected by micro-CT represented limitations of this study. Our model showed that an intra-operative low-grade S. epidermidis contamination might prevent the bone healing, even in the absence of infectious signs. Our findings also pointed out a dose-dependent effect between the S. epidermidis inoculum and non-union rate. This pilot study identifies a relevant preclinical model to assess the role of subclinical infections in orthopaedic and trauma surgery and to test specifically designed diagnostic, prevention and therapeutic strategies.

α-Melanocyte-stimulating-hormone (α-MSH) modulates human chondrocyte activation induced by proinflammatory cytokines.

BACKGROUND: Alpha-melanocyte-stimulating-hormone (α-MSH) has marked anti-inflammatory potential. Proinflammatory cytokines are critical mediators of the disturbed cartilage homeostasis in osteoarthritis, inhibiting anabolic activities and increasing catabolic activities in chondrocytes. Since human chondrocytes express α-MSH receptors, we evaluated the role of the peptide in modulating chondrocyte production of pro-inflammatory cytokines, matrix metalloproteinases (MMPs), tissue inhibitors of MMPs (TIMPs), inducible nitric oxide synthase (iNOS) and nitric oxide (NO) in response to interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α). METHODS: Human articular chondrocytes were obtained from osteoarthritic joint cartilage from subjects undergoing hip routine arthroplasty procedures. The cells were cultured with or without α-MSH in the presence of IL-1ß or TNF-α. Cell-free supernatants were collected and cells immediately lysed for RNA purification. Expression of cytokines, MMPs, TIMPs, iNOS was determined by Reverse Transcription Real-time Polymerase Chain Reaction and enzyme-linked immunosorbent assay. Griess reaction was used for NO quantification. RESULTS: Gene expression and secretion of IL-6, IL-8, MMP-3, MMP-13 were significantly increased in IL-1ß or TNF-α-stimulated chondrocytes; α-MSH did not modify the release of IL-6 or IL-8 while the peptide significantly reduced their gene expression on TNF-α-stimulated cells. A significant inhibition of MMP3 gene expression and secretion from IL-1ß or TNFα-stimulated chondrocytes was induced by α-MSH. On the other hand, α-MSH did not modify the release of MMP-13 by cytokine-stimulated chondrocyte but significantly decreased gene expression of the molecule on TNF-α-stimulated cells. Detectable amount of TIMP-3 and TIMP-4 were present in the supernatants of resting chondrocytes and a significant increase of TIMP-3 gene expression and release was induced by α-MSH on unstimulated cells. TIMP-3 secretion and gene expression were significantly increased in IL-1ß-stimulated chondrocytes and α-MSH down-regulated gene expression but not secretion of the molecule. TIMP-4 gene expression (but not secretion) was moderately induced in IL-1ß-stimulated chondrocytes with a down-regulation exerted by α-MSH. IL-1ß and TNF-α were potent stimuli for NO production and iNOS gene expression by chondrocytes; no inhibition was induced by α-MSH on cytokine-stimulated NO production, while the peptide significantly reduced gene expression of iNOS. CONCLUSIONS: Our results underscore a potential anti-inflammatory and chondroprotective activity exerted by α-MSH, increasing TIMP-3 gene expression and release on resting cells and down- modulating TNF-α-induced activation of human chondrocytes. However, the discrepancy between the influences exerted by α-MSH on gene expression and protein release as well as the difference in the inhibitory pattern exerted by α-MSH in TNF-α- or IL-1ß-stimulated cells leave some uncertainty on the role of the peptide on chondrocyte modulation.