JTE-952 Suppresses Bone Destruction in Collagen-Induced Arthritis in Mice by Inhibiting Colony Stimulating Factor 1 Receptor.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial inflammation and structural destruction of the joints. Bone damage occurs in an early stage after onset and osteoclast activation plays a substantial role in its progression. Colony stimulating factor 1 receptor (CSF1R) is a receptor protein tyrosine kinase specifically expressed in monocytic-lineage cells such as macrophages and osteoclasts. Here, we investigated the effect of JTE-952, a novel CSF1R tyrosine kinase inhibitor, on osteoclast formation in vitro and on bone destruction in a mouse model of collagen-induced arthritis. JTE-952 completely inhibited osteoclast differentiation from human monocytes, with an IC50 of 2.8 nmol/L, and reduced osteoclast formation from the synovial cells of RA patients. Detectable levels of colony stimulating factor 1 (CSF1), a ligand of CSF1R, were observed in the synovial tissues of the arthritis model, similar to those observed in the pathology of human RA. JTE-952 significantly suppressed increases in the bone destruction score, the number of tartrate-resistant-acid-phosphatase-positive cells, and the severity of arthritis in the model mice. We also examined the efficacy of JTE-952 combined with methotrexate. This combination therapy more effectively reduced the severity of bone destruction and arthritis than monotherapy with either agent alone. In summary, JTE-952 potently inhibited human osteoclast formation in vitro and suppressed bone destruction in an experimental arthritis model, especially when combined with methotrexate. These results indicate that JTE-952 should strongly inhibit bone destruction and joint inflammation in RA patients and effectively prevent the progression of the structural destruction of joints.

Role of endogenous androgen against insulin resistance and athero- sclerosis in men with type 2 diabetes.

Age-related decline in serum testosterone and dehydroepiandrosterone sulfate concentrations occur in men. Low concentrations of these endogenous androgens have been linked with insulin resistance, which is an important upstream driver for metabolic abnormalities such as hyperglycemia, hypertension, or hyperlipidemia, and increased cardiovascular risk. Moreover, men with diabetes have significantly less circulating androgen than nondiabetic men. Here, we summarize how androgen affects insulin resistance and atherosclerosis in men with type 2 diabetes. Low serum concentrations of endogenous androgens are associated with visceral fat accumulation. Androgen deprivation by castration to treat prostate cancer increases insulin resistance, while testosterone administration in type 2 diabetic men with androgen deficiency improves glucose homeostasis and decreases visceral fat, in addition to alleviating symptoms of androgen deficiency including erectile dysfunction. Androgen correlates inversely with severity of atherosclerosis and has beneficial effects upon vascular reactivity, inflammatory cytokine, adhesion molecules, insulin resistance, serum lipids, and hemostatic factors. Because men with type 2 diabetes have relative hypogonadism, testosterone supplementation could decrease both insulin resistance and atherosclerosis.