Objective To investigate the impact of systemic inhibition of interleukin 6 (IL-6) or signal transducer and activator of transcription (Stat3) in an experimental model of osteoarthritis (OA). Methods Expression of major catabolic and anabolic factors of cartilage was determined in IL-6-treated mouse chondrocytes and cartilage explants. The anti-IL-6-receptor neutralising antibody MR16-1 was used in the destabilisation of the medial meniscus (DMM) mouse model of OA. Stat3 blockade was investigated by the small molecule Stattic ex vivo and in the DMM model. Results In chondrocytes and cartilage explants, IL-6 treatment reduced proteoglycan content with increased production of matrix metalloproteinase (MMP-3 and MMP-13) and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS-4 and ADAMTS-5). IL-6 induced Stat3 and extracellular signal-regulated kinase (ERK) 1/2 signalling but not p38, c-Jun N-terminal kinase or Akt. In the DMM model, Stat3 was activated in cartilage, but neither in the synovium nor in the subchondral bone. Systemic blockade of IL-6 by MR16-1 alleviated DMM-induced OA cartilage lesions, impaired the osteophyte formation and the extent of synovitis. In the same model, Stattic had similar beneficial effects on cartilage and osteophyte formation. Stattic, but not an ERK1/2 inhibitor, significantly counteracted the catabolic effects of IL-6 on cartilage explants and suppressed the IL-6-induced chondrocytes apoptosis. Conclusion IL-6 induces chondrocyte catabolism mainly via Stat3 signalling, a pathway activated in cartilage from joint subjected to DMM. Systemic blockade of IL-6 or STAT-3 can alleviate DMM-induced OA in mice.

Mineral and bone disease is omnipresent in patients with chronic kidney disease (CKD) and leads to a diverse range of clinical manifestations, including bone pain and fractures. The accumulation of traditional clinical risk factors, in addition to those related to CKD, enhances the risk of comorbidity and mortality. Despite significant advances in understanding bone disease in CKD, most clinical and biochemical targets used in clinical practice remain controversial, resulting in an undermanagement of bone fragility. Vitamin D supplementation is widely used, but only a few studies have shown beneficial effects and a reduced risk of fracture and mortality. The achievement of serum levels of 25-hydroxyvitamin D is recommended for CKD patients to reduce a high parathyroid hormone level, which is associated with skeletal fractures. Optimal control of parathyroid hormone also improves bone mineralization and lowers circulating bone biomarkers such as alkaline phosphatase and cross-linked collagen type I peptide. The potential value of more recent biomarkers such as sclerostin and fibroblast growth factor 23, as surrogates for bone fragility, is an encouraging new direction in clinical research but is far from being firmly established. This article reviews the literature related to the pathophysiological role of various mineral and biochemical factors involved in renal osteodystrophy. To better understand bone fragility in CKD, new information related to the impact of disturbances of mineral metabolism on bone strength is urgently needed. The combined expertise of clinicians from various medical disciplines appears crucial for the most successful prevention of fractures in these patients.

Osteoporosis is one of the most common degenerative diseases. It is characterized by reduced bone mineral density (BMD) with an increased risk for bone fractures. There is a substantial genetic contribution to BMD, although the genetic factors involved in the pathogenesis of human osteoporosis are largely unknown. Mice with a targeted deletion of either the cannabinoid receptor type 1 (Cnr1) or type 2 (Cnr2) gene show an alteration of bone mass, and pharmacological modification of both receptors can regulate osteoclast activity and BMD. We therefore analyzed both genes in a systematic genetic association study in a human sample of postmenopausal osteoporosis patients and matched female controls. We found a significant association of single polymorphisms (P=0.0014) and haplotypes (P=0.0001) encompassing the CNR2 gene on human chromosome 1p36, whereas we found no convincing association for CNR1. These results demonstrate a role for the peripherally expressed CB2 receptor in the etiology of osteoporosis and provide an interesting novel therapeutical target for this severe and common disease.

OUR UNDERSTANDING of the pathogenesis of bone disorders has progressed considerably over the past 20 years. In individuals with normal kidney function, the focus has predominantly been on osteoporosis, whereas in individuals with impaired kidney function, the focus has been on the condition referred to as renal osteodystrophy. This pathologic understanding has led to significant advances in the therapy of bone disease as it affects these patient populations. Although these advances have tended to occur in parallel, there has been relatively little integration between the two.

Objective Macrophage activation by monosodium urate (MSU) and calcium pyrophosphate (CPP) crystals mediates an interleukin (IL)-1β-dependent inflammation during gout and pseudo-gout flare, respectively. Since metabolic reprogramming of macrophages goes along with inflammatory responses dependently on stimuli and tissue environment, we aimed to decipher the role of glycolysis and oxidative phosphorylation in the IL-1β-induced microcrystal response. Methods Briefly, an in vitro study (metabolomics and real-time extracellular flux analysis) on MSU and CPP crystal-stimulated macrophages was performed to demonstrate the metabolic phenotype of macrophages. Then, the role of aerobic glycolysis in IL-1β production was evaluated, as well in vitro as in vivo using ¹⁸F-fluorodeoxyglucose positron emission tomography imaging and glucose uptake assay, and molecular approach of glucose transporter 1 (GLUT1) inhibition. Results We observed that MSU and CPP crystals led to a metabolic rewiring toward the aerobic glycolysis pathway explained by an increase in GLUT1 plasma membrane expression and glucose uptake on macrophages. Also, neutrophils isolated from human synovial fluid during gout flare expressed GLUT1 at their plasma membrane more frequently than neutrophils isolated from bloodstream. Both glucose deprivation and treatment with either 2-deoxyglucose or GLUT1 inhibitor suppressed crystal-induced NLRP3 activation and IL-1β production, and microcrystal inflammation in vivo. Conclusion In conclusion, we demonstrated that GLUT1-mediated glucose uptake is instrumental during the inflammatory IL-1β response induced by MSU and CPP crystals. These findings open new therapeutic paths to modulate crystal-related inflammation.