The mobilization and extracellular release of nuclear high mobility group box-1 (HMGB1) by ischemic cells activates inflammatory pathways following liver ischemia/reperfusion (I/R) injury. In immune cells such as macrophages, post-translational modification by acetylation appears to be critical for active HMGB1 release. Hyperacetylation shifts its equilibrium from a predominant nuclear location toward cytosolic accumulation and subsequent release. However, mechanisms governing its release by parenchymal cells such as hepatocytes are unknown. In this study, we found that serum HMGB1 released following liver I/R in vivo is acetylated, and that hepatocytes exposed to oxidative stress in vitro also released acetylated HMGB1. Histone deacetylases (HDACs) are a family of enzymes that remove acetyl groups and control the acetylation status of histones and various intracellular proteins. Levels of acetylated HMGB1 increased with a concomitant decrease in total nuclear HDAC activity, suggesting that suppression in HDAC activity contributes to the increase in acetylated HMGB1 release after oxidative stress in hepatocytes. We identified the isoforms HDAC1 and HDAC4 as critical in regulating acetylated HMGB1 release. Activation of HDAC1 was decreased in the nucleus of hepatocytes undergoing oxidative stress. In addition, HDAC1 knockdown with siRNA promoted HMGB1 translocation and release. Furthermore, we demonstrate that HDAC4 is shuttled from the nucleus to cytoplasm in response to oxidative stress, resulting in decreased HDAC activity in the nucleus. Together, these findings suggest that decreased nuclear HDAC1 and HDAC4 activities in hepatocytes following liver I/R is a mechanism that promotes the hyperacetylation and subsequent release of HMGB1. High Mobility Group Box Protein 1 (HMGB1)3 is a ubiquitously expressed nuclear molecule that functions as a structural protein of chromatin (1). In addition to its nuclear role, HMGB1 also functions as an inflammatory cytokine when released from necrotic cells or actively secreted from stressed cells. Its proinflammatory properties were first highlighted in experiments showing that HMGB1 is actively secreted by activated macrophages, serving as a late mediator of lethality in sepsis (2). Whereas HMGB1 is involved in the late systemic inflammatory response to sepsis, our laboratory demonstrated that HMGB1 is a central and necessary mediator of organ damage following acute, sterile organ injury (3, 4). HMGB1 is rapidly mobilized and released by hepatocytes in the setting of hepatic ischemia and reperfusion injury. Extracellular HMGB1 functions as a damage-associated molecular pattern (DAMP) molecule and activates proinflammatory signaling pathways by activating pattern recognition receptors including Toll-like receptor 4 (TLR4) and the receptor for advanced glycation end-products (RAGE) (5, 6). Mounting evidence suggests HMGB1 may also function to facilitate the recognition of other immune co-activators such as LPS, DNA, and IL-1 through avid binding to these molecules (7-9).Thoro...

Biologic therapies, including stem cells, platelet-rich plasma, growth factors, and other biologically active adjuncts, have recently received increased attention in the basic science and clinical literature. At the 2015 AOSSM Biologics II Think Tank held in Colorado Springs, Colorado, a group of orthopaedic surgeons, basic scientists, veterinarians, and other investigators gathered to review the state of the science for biologics and barriers to implementation of biologics for the treatment of sports medicine injuries. This series of current concepts reviews reports the summary of the scientific presentations, roundtable discussions, and recommendations from this think tank.

Purpose Distal femur morphology has been shown to inluence knee joint kinematics and may afect rotatory knee laxity. The purpose of this study was to determine the relationship between rotatory knee laxity and distal femoral morphology in patients with complete anterior cruciate ligament (ACL) rupture. It was hypothesized that increased posterior femoral condylar depth on standard lateral radiographs, quantiied as the "lateral femoral condyle ratio" would correlate with increased rotatory knee laxity, measured by a quantitative pivot shift test. Methods Consecutive patients who underwent ACL reconstruction from 2014 to 2016 were retrospectively reviewed. A standardized pivot shift test was performed preoperatively on both knees and quantiied using tablet technology. Using standard lateral radiographs of the knee, the ratio of posterior condylar distance over total condylar distance was deined as the lateral femoral condyle ratio. Results Data sets were obtained for 57 patients. The mean anterior translation of the lateral knee compartment during a quantitative pivot shift test was found to be 4.0 ± 2.4 mm and 1.3 ± 0.9 mm for the injured and uninjured knees, respectively. The mean lateral femoral condyle ratio on X-ray was 63.2 ± 4.5%. There were signiicant correlations between the lateral femoral condyle ratio and the absolute quantitative (ρ = 0.370, p < 0.05) and side-to-side diferences in anterior translation of the lateral knee compartment (ρ = 0.419, p < 0.05). ConclusionThe most important inding from this study is that increased posterior femoral condylar depth, quantiied as a lateral femoral condyle ratio, is associated with increased rotatory knee laxity in ACL-deicient patients. This suggests that distal femur morphology may inluence rotatory knee laxity. This study may assist clinicians in evaluating ACL injuries and identifying patients at greater risk for persistent increased rotatory knee laxity after ACL reconstruction. Level of evidence III.

Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Rotator cuff tears are common and result in considerable morbidity. Tears within the tendon substance or at its insertion into the humeral head represent a considerable clinical challenge because of the hostile local environment that precludes healing. Tears often progress without intervention, and current surgical treatments are inadequate. Although surgical implants, instrumentation, and techniques have improved, healing rates have not improved, and a high failure rate remains for large and massive rotator cuff tears. The use of biologic adjuvants that contribute to a regenerative microenvironment have great potential for improving healing rates and function after surgery. This article presents a review of current and emerging biologic approaches to augment rotator cuff tendon and muscle regeneration focusing on the scientific rationale, preclinical, and clinical evidence for efficacy, areas for future research, and current barriers to advancement and implementation.

For shorter duration symptoms, tissue-specific stretching and conditioning methods were favored over anti-inflammatory or structural support modalities which is consistent with available high-level evidence studies. Heterogeneity of operative preferences for chronic symptoms highlighted the need for further high-quality studies.

Focal chondral defects of the articular surface are a common occurrence in the field of orthopaedics. These isolated cartilage injuries, if not repaired surgically with restoration of articular congruency, may have a high rate of progression to posttraumatic osteoarthritis, resulting in significant morbidity and loss of function in the young, active patient. Both isolated and global joint disease are a difficult entity to treat in the clinical setting given the high amount of stress on weightbearing joints and the limited healing potential of native articular cartilage. Recently, clinical interest has focused on the use of biologically active compounds and surgical techniques to regenerate native cartilage to the articular surface, with the goal of restoring normal joint health and overall function. This article presents a review of the current biologic therapies, as discussed at the 2015 American Orthopaedic Society for Sports Medicine (AOSSM) Biologics Think Tank, that are used in the treatment of focal cartilage deficiencies. For each of these emerging therapies, the theories for application, the present clinical evidence, and specific areas for future research are explored, with focus on the barriers currently faced by clinicians in advancing the success of these therapies in the clinical setting.

Motion at the knee joint is a complex mechanical phenomenon. Stability is provided by a combination of static and dynamic structures that work in concert to prevent excessive movement or instability that is inherent in various knee injuries. The anterior cruciate ligament (ACL) is a main stabilizer of the knee, providing both translational and rotatory constraint. Despite the high volume of research directed at native ACL function, pathogenesis and surgical reconstruction of this structure, a gold standard for objective quantification of injury and subsequent repair, has not been demonstrated. Furthermore, recent studies have suggested that novel anatomic structures may play a significant role in knee stability. The use of biomechanical principles and testing techniques provides essential objective/quantitative information on the function of bone, ligaments, joint capsule, and other contributing soft tissues in response to various loading conditions. This review discusses the principles of biomechanics in relation to knee stability, with a focus on the objective quantification of knee stability, the individual contributions of specific knee structures to stability, and the most recent technological advances in the biomechanical evaluation of the knee joint.