Identification of formulation parameters that affect the analgesic efficacy of ProGel-Dex - A thermoresponsive polymeric dexamethasone prodrug for chronic arthritis pain relief.

The relief of joint pain is one of the main objectives in the clinical management of arthritis. Although significant strides have been made in improving management of rheumatoid and related forms of inflammatory arthritis, there are still major unmet needs for therapies that selectively provide potent, sustained and safe joint pain relief, especially among patients with osteoarthritis (OA), the most common form of arthritis. We have recently developed ProGel-Dex, an N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer-based thermoresponsive dexamethasone (Dex) prodrug, which forms a hydrogel upon intra-articular administration and provides sustained improvement in pain-related behavior and inflammation in rodent models of arthritis.

PTH treatment before cyclic joint loading improves cartilage health and attenuates load-induced osteoarthritis development in mice.

Osteoarthritis (OA) treatment is limited by the lack of effective nonsurgical interventions to slow disease progression. Here, we examined the contributions of the subchondral bone properties to OA development. We used parathyroid hormone (PTH) to modulate bone mass before OA initiation and alendronate (ALN) to inhibit bone remodeling during OA progression.

Thermoresponsive Polymeric Hydromorphone Prodrug Provides Sustained Local Analgesia without Apparent Adverse Effects.

The extensive use of opioids for chronic pain management has contributed significantly to the current opioid epidemic. While many alternative nonopioid analgesics are available, opioids remain the most potent analgesics for moderate to severe pain management. In addition to the implementation of multimodal analgesia, there is a pressing need for the development of more effective and safer opioids.

Single dose thermoresponsive dexamethasone prodrug completely mitigates joint pain for 15 weeks in a murine model of osteoarthritis.

In this study, we aimed to assess the analgesic efficacy of a thermoresponsive polymeric dexamethasone (Dex) prodrug (ProGel-Dex) in a mouse model of osteoarthritis (OA). At 12 weeks post model establishment, the OA mice received a single intra-articular (IA) injection of ProGel-Dex, dose-equivalent Dex, or Saline. Comparing to Saline and Dex controls, ProGel-Dex provided complete and sustained pain relief for >15 weeks according to incapacitance tests.

Integrin-dependent recruitment of Src to ROS-producing endosomes in osteoarthritic cartilage.

Fibronectin (FN) fragments stimulate catabolic signaling, and, by binding to integrins, they induce chondrocytes to increase the production of matrix metalloproteinases, including MMP-13. In this issue of , Miao reveal that internalization of a FN fragment, but not intact FN, by α5β1 integrin results in the formation of ROS-producing endosomes (redoxosomes) through which chondrocytes detect and respond to damaged matrix by producing more MMP-13.

Superior Sternoclavicular Dislocation Treated with Costoclavicular Ligament Reconstruction Using Autograft: A Case Report.

Case: We describe a case of a traumatic superior dislocation of the sternoclavicular joint (SCJ) due to an isolated rupture of the costoclavicular ligament (CCL). A magnetic resonance imaging (MRI) scan demonstrated the CCL rupture with preservation of the anterior and posterior SCJ ligaments. This was successfully treated with an isolated hamstring tendon reconstruction of the CCL, resulting in a satisfactory outcome at 1 year after the procedure.

Contribution of joint tissue properties to load-induced osteoarthritis.

Objective: Clinical evidence suggests that abnormal mechanical forces play a major role in the initiation and progression of osteoarthritis (OA). However, few studies have examined the mechanical environment that leads to disease. Thus, using a mouse tibial loading model, we quantified the cartilage contact stresses and examined the effects of altering tissue material properties on joint stresses during loading.

Macroscopic Synovial Inflammation Correlates with Symptoms and Cartilage Lesions in Patients Undergoing Arthroscopic Partial Meniscectomy: A Clinical Study.

Background: The aim of the study was to examine the relationship among patients' characteristics, intraoperative pathology and pre/post-operative symptoms in a cohort of patients undergoing arthroscopic partial meniscectomy for symptomatic meniscal tears.

Methods: Clinical data were collected (age, sex, body mass index, time to surgery, trauma). Intraoperative cartilage pathology was assessed with Outerbridge score.

Shared Reality Can Reduce Stressor Reactivity.

When a person faces a stressor alongside someone else, do they get more or less stressed when the other person agrees that the situation is stressful? While an equally stressed partner could plausibly amplify stress by making the situation seem more real and worthy of distress, we find that social validation during co-experienced stressors reduces reactivity. Specifically, the psychological experience of shared reality calms some people down. In Study 1, 70 undergraduate females who jointly faced a stressful event with someone else reported feeling less anxious when the other person felt the same way about the stressor, relative to when the other person appraised the situation in the opposite way or provided no indication of their appraisal.

Do Synovial Inflammation and Meniscal Degeneration Impact Clinical Outcomes of Patients Undergoing Arthroscopic Partial Meniscectomy? A Histological Study.

The menisci exert a prominent role in joint stabilization and in the distribution of mechanical loading. Meniscal damage is associated with increased risk of knee OA. The aim of this study was to characterize the synovial membrane and meniscal tissues in patients undergoing arthroscopic partial meniscectomy for meniscal tear and to evaluate association with clinical outcomes.

Physical effects of daily stressors are psychologically mediated, heterogeneous, and bidirectional.

Prior research shows that daily stressors lead to greater psychological distress. A separate body of research links daily stressors to physical symptoms such as backaches and stomach problems. We integrate these literatures by positing an interconnected causal system, whereby stressors lead to psychological distress which, in turn, leads to physical symptoms.

Transcriptomic and epigenomic analyses uncovered Lrrc15 as a contributing factor to cartilage damage in osteoarthritis.

In osteoarthritis (OA), articular chondrocytes display phenotypic and functional changes associated with epigenomic alterations. These changes contribute to the disease progression, which is characterized by dysregulated reparative processes and abnormal extracellular matrix remodeling leading to cartilage degradation. Recent studies using a murine model of posttraumatic OA highlighted the contribution of changes in DNA hydroxymethylation (5hmC) to OA progression.

Thermoresponsive polymeric dexamethasone prodrug for arthritis pain.

Intra-articular (IA) glucocorticoids (GC) are commonly used for clinical management of both osteoarthritis and rheumatoid arthritis, but their efficacy is limited by the relatively short duration of action and associated side effects. To provide sustained efficacy and to improve the safety of GCs, we previously developed a N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-based dexamethasone (Dex) prodrug. Serendipitously, we discovered that, by increasing the Dex content of the prodrug to unusually high levels, the aqueous solution of the polymeric prodrug becomes thermoresponsive, transitioning from a free-flowing liquid at 4 °C to a hydrogel at 30 °C or greater.

Mood and judgment in a dyadic stress context.

The 1980s and 1990s witnessed a surge of psychological research addressing the role of affect in social judgments. Evaluations of others were shown to be shaped, at least in part, by a person's incidental mood in the moment of social evaluation; while negative moods instigated negative interpersonal evaluations, positive moods instigated positive interpersonal evaluations. Interestingly, these effects only emerged when the reason for the evaluator's mood was not obvious.

Mothers' and fathers' cognitive and affective responses to epigenetics concepts.

Advances in our understanding of epigenetics present new opportunities to improve children's health through the counseling of parents about epigenetics concepts. However, it is important to first evaluate how parents respond to this type of information and determine the consequences of educating parents about epigenetics. We have taken an initial step toward this goal by assessing parental responses to an epigenetics learning module.

LOXL2 promotes aggrecan and gender-specific anabolic differences to TMJ cartilage.

In the United States, 5-12% of adults have at least one symptom of temporomandibular joint (TMJ) disorders, including TMJ osteoarthritis (TMJ-OA). However, there is no chondroprotective agent that is approved for clinical application. We showed that LOXL2 is elevated in the regenerative response during fracture healing in mice and has a critical role in chondrogenic differentiation.

Investigating the Efficacy of Genetic, Environmental, and Multifactorial Risk Information When Communicating Obesity Risk to Parents of Young Children.

Background: Effectively communicating with parents about children's obesity risk is of critical importance for preventive medicine and public health.

Purpose: The current study investigates the efficacy of communications focused on two primary causes of obesity: genes and environment.

Methods: We compared parental feeding responses to messages focused on (i) genetics alone, (ii) family environment alone, (iii) genetics-family environment interaction (G × FE), and (iv) no causal message.

Mouse Models of Osteoarthritis: Surgical Model of Post-traumatic Osteoarthritis Induced by Destabilization of the Medial Meniscus.

The surgical model of destabilization of the medial meniscus (DMM) has become a gold standard for studying the onset and progression of post-traumatic osteoarthritis (OA). The DMM model mimics clinical meniscal injury, a known predisposing factor for the development of human OA, and permits the study of structural and biological changes over the course of the disease. In addition, when applied to genetically modified or engineered mouse models, this surgical procedure permits dissection of the relative contribution of a given gene to OA initiation and/or progression.

The integrative analysis of DNA methylation and mRNA expression profiles confirmed the role of selenocompound metabolism pathway in Kashin-Beck disease.

Kashin-Beck disease (KBD) is an endemic chronic osteochondropathy. The etiology of KBD remains unknown. In this study, we conducted an integrative analysis of genome-wide DNA methylation and mRNA expression profiles between KBD and normal controls to identify novel candidate genes and pathways for KBD.

Labral calcification plays a key role in hip pain and symptoms in femoroacetabular impingement.

Background: Hip osteoarthritis (HOA) is the most common hip disorder and a major cause of disability in the adult population, with an estimated prevalence of end-stage disease and total hip replacement. Thus, the diagnosis, prevention, and treatment of the early stages of the disease in young adults are crucial to reduce the incidence of end-stage HOA. The purpose of this study was to determine whether (1) a relationship among the inflammatory status of labrum and synovium collected from patients with femoroacetabular impingement (FAI) would exist; and (2) to investigate the associations among the histopathological features of joint tissues, the pre-operative symptoms and the post-operative outcomes after arthroscopic surgery.

Lysyl Oxidase-Like 2 Protects against Progressive and Aging Related Knee Joint Osteoarthritis in Mice.

Background: The goal of this study was to determine if adenovirus-delivered LOXL2 protects against progressive knee osteoarthritis (OA), assess its specific mechanism of action; and determine if the overexpression of LOXL2 in transgenic mice can protect against the development of OA-related cartilage damage and joint disability.

Methods: Four-month-old Cho/+ male and female mice were intraperitoneally injected with either Adv-RFP-LOXL2 or an empty vector twice a month for four months. The proteoglycan levels and the expression of anabolic and catabolic genes were examined by immunostaining and qRT-PCR.

Inducible knockout of CHUK/IKKα in adult chondrocytes reduces progression of cartilage degradation in a surgical model of osteoarthritis.

CHUK/IKKα contributes to collagenase-driven extracellular matrix remodeling and chondrocyte hypertrophic differentiation in vitro, in a kinase-independent manner. These processes contribute to osteoarthritis (OA), where chondrocytes experience a phenotypic shift towards hypertrophy concomitant with abnormal matrix remodeling. Here we investigated the contribution of IKKα to OA in vivo.

Parental Defensiveness about Multifactorial Genomic and Environmental Causes of Children's Obesity Risk.

Future integration of genomics into weight management may target children with overweight given prospects for prevention. Meanwhile, parents learn about weight-related genomics primarily through the media, and little is known about parental reactions to complex genomic and environmental causes underlying children's obesity risk. Three hundred twenty-four parents with overweight who have a child 3-13 years of age were recruited through Amazon Mechanical Turk.