Interferon-gamma signaling promotes cartilage regeneration after injury.

Osteoarthritis is a common chronic disease and major cause of disability and chronic pain in ageing populations. In this pathology, the entire joint is involved, and the regeneration of articular cartilage still remains one of the main challenges. Here, we investigated the molecular mechanisms underlying cartilage regeneration in young mice using a full-thickness cartilage injury (FTCI) model. FTCI-induced cartilage defects were created in the femoral trochlea of young and adult C57BL/6 mice. To identify key molecules and pathways involved in the early response to cartilage injury, we performed RNA sequencing (RNA-seq) analysis of cartilage RNA at 3 days after injury. Young mice showed superior cartilage regeneration compared to adult mice after cartilage injury. RNA-seq analysis revealed significant upregulation of genes associated with the immune response, particularly in the IFN-γ signaling pathway and qRT-PCR analysis showed macrophage polarization in the early phase of cartilage regeneration (3 days) in young mice after injury, which might promote the removal of damaged or necrotic cells and initiate cartilage regeneration in response to injury. IFN-γR1- and IFN-γ-deficient mice exhibited impaired cartilage regeneration following cartilage injury. DMM-induced and spontaneous OA phenotypes were exacerbated in IFN-γR1-/- mice than in wild-type mice. Our data support the hypothesis that IFN-γ signaling is necessary for cartilage regeneration, as well as for the amelioration of post-traumatic and age-induced OA.

A causative role for periarticular skeletal muscle weakness in the progression of joint damage and pain in OA.

Although osteoarthritis (OA) is regarded as a disease of the articular cartilage, recent research has demonstrated alterations in periarticular muscles that surround the affected joint. Here, we investigated changes in periarticular muscle during the progression of OA, as well as the cause-and-effect relationship between muscle weakness and OA, in a mouse model of OA by destabilization of the medial meniscus (DMM). Pathological phenotypes in the periarticular muscles were assessed in the early and late stages of OA by DMM. OA pathology and pain behavior in the mice after DMM induction were examined in response to periarticular muscle weakness induced by multiple rounds of barium chloride (BaCl2) injections. The examinations were also performed in myostatin knockout mice with strengthened muscle phenotypes by muscle hypertrophy. Morphological alterations in the tibialis anterior (TA) and quadriceps muscles in DMM mice included variations in muscle-fiber size, aberrant extracellular matrix (ECM) deposition, inflammatory cell infiltration, and decreased muscle mass. Periarticular muscle fibers isolated from DMM mice showed reductions in the number of satellite cells and myogenic capacity of primary myoblast, as well as proliferation. DMM + muscle injury mice also showed exacerbated joint degeneration compared to the DMM vehicles. Myostatin knockout mice were characterized by attenuated OA and the complete abrogation of pain behavior after DMM. Our results suggest an association between muscle weakness and OA progression and pain.

Study of the correlations between fractional exhaled nitric oxide in exhaled breath and atopic status, blood eosinophils, FCER2 mutation, and asthma control in Vietnamese children.

INTRODUCTION: Fractional exhaled nitric oxide (FENO) is a biomarker of airway inflammation in asthma. The measurement of FENO is utilized to assist in the diagnosis and treatment of children with asthma, especially for those treated with inhaled corticosteroids. OBJECTIVES: The aims of this study were to evaluate the correlations between FENO and atopic status, blood eosinophil levels, FCER2 mutation, and asthma control in Vietnamese children. SUBJECTS AND METHODS: This was a prospective and descriptive study approved by the local Ethical Board. All children with uncontrolled asthma, seen in the National Hospital of Pediatrics (Hanoi, Vietnam), were included. Exhaled breath FENO, blood eosinophils, skin prick test, total IgE, asthma control test (ACT), and FCER2 gene polymorphism were performed at inclusion. They were followed up at 3 months to evaluate clinical status, FENO levels, and ACT. RESULTS: Forty-two children with uncontrolled asthma with a mean age of 10±3 years (6-16 years) were included. The male/female ratio was 2.5/1. The mean FENO levels were 26±25 ppb. FENO was significantly higher in patients with a positive skin prick test for respiratory allergens (P<0.05). FENO was significantly correlated with blood eosinophil levels (r=0.5217; P=0.0004). Five of the 32 subjects (15.6%) had a mutation of FCER2 gene (rs28364072 SNP). In this group, the levels of FENO were highest (37±10 ppb; P<0.05). The levels of FENO were significantly decreased after 3 months of treatment (17±8 ppb vs 26±25 ppb; P<0.05). Significant correlations between inhaled corticosteroid doses and FENO levels occurred at 1 and 3 months (r=0.415, P=0.007; r=0.396, P=0.010; respectively). There were no correlations between FENO levels, ACT, and daily use of salbutamol. After 3 months, asthma remained uncontrolled in 22.2% of children. CONCLUSION: The measurement of FENO levels is a useful and feasible tool to predict clinical, biological, and asthma control in Vietnamese children.