Osteoclast precursor differentiation by MCPIP via oxidative stress,endoplasmic reticulum stress,and autophagy

Osteoclasts(OCs)are responsible for bone resorption in inflammatory joint diseases.Monocyte chemotactic protein-1(MCP-1)has been shown to induce differentiation of monocytes to OC precursors,but nothing is known about the underlying mechanisms.Here,we elucidate how MCPIP,induced by MCP-1,mediates this differentiation.Knockdown of MCPIP abolished MCP-1-mediated expression of OC markers,tartrate-resistant acid phosphatase,and serine protease cathepsin K.Expression of MCPIP induced p47PHOX and its membrane translocation,reactive oxygen species formation,and induction of endoplasmic reticulum(ER)stress chaperones,up-regulation of autophagy marker,Beclin-1,and lipidation of LC3,and induction of OC markers.Inhibition of oxidative stress attenuated ER stress and autophagy,and suppressed expression of OC markers.Inhibition of ER stress by a specific inhibitor or by knockdown of IRE1 blocked autophagy and induction of OC markers.ER stress inducers,tunicamycin and thapsigargin,induced expression of OC markers.Autophagy inhibition by 3′-methyladenine,LY294002,wortmannin or by knockdown of Beclin-1 or Atg 7 inhibited MCPIP-induced expression of OC markers.These results strongly suggest that MCP-1-induced differentiation of OC precursor cells is mediated via MCPIP-induced oxidative stress that causes ER stress leading to autophagy,revealing a novel mechanistic insight into the role of MCP-1 in OCs differentiation.

Interaction between stress responses and circadian metabolism in metabolic disease

Circadian rhythms play crucial roles in orchestrating diverse physiological processes that are critical for health and disease.Dysregulated circadian rhythms are closely associated with various human metabolic diseases,including type 2 diabetes,cardiovascular disease,and non-alcoholic fatty liver disease.Modern lifestyles are frequently associated with an irregular circadian rhythm,which poses a significant risk to public health.While the central clock has a set periodicity,circadian oscillators in peripheral organs,particularly in the liver,can be entrained by metabolic alterations or stress cues.At the molecular level,the signal transduction pathways that mediate stress responses interact with the key determinants of circadian oscillation to maintain metabolic homeostasis under physiological or pathological conditions.In the liver,a number of nuclear receptors or transcriptional regulators,which are regulated by metabolites,hormones,the circadian clock,or environmental stressors,serve as direct links between stress responses and circadian metabolism.In this review,we summarize recent advances in the understanding of the interactions between stress responses(endoplasmic reticulum stress response,oxidative stress response,and inflammatory responses)and circadian metabolism,and the role of these interactions in the development of metabolic diseases.