The JAK1/STAT3/SOCS3 axis in bone development, physiology, and pathology

Bone growth and the maintenance of bone structure are controlled by multiple endocrine and paracrine factors, including cytokines expressed locally within the bone microenvironment and those that are elevated, both locally and systemically, under inflammatory conditions. This review focuses on those bone-active cytokines that initiate JAK–STAT signaling, and outlines the discoveries made from studying skeletal defects caused by induced or spontaneous modifications in this pathway. Specifically, this review describes defects in JAK1, STAT3, and SOCS3 signaling in mouse models and in humans, including mutations designed to modify these pathways downstream of the gp130 coreceptor. It is shown that osteoclast formation is generally stimulated indirectly by these pathways through JAK1 and STAT3 actions in inflammatory and other accessory cells, including osteoblasts. In addition, in bone remodeling, osteoblast differentiation is increased secondary to stimulated osteoclast formation through an IL-6-dependent pathway. In growth plate chondrocytes, STAT3 signaling promotes the normal differentiation process that leads to bone lengthening. Within the osteoblast lineage, STAT3 signaling promotes bone formation in normal physiology and in response to mechanical loading through direct signaling in osteocytes. This activity, particularly that of the IL-6/gp130 family of cytokines, must be suppressed by SOCS3 for the normal formation of cortical bone. Bone: signaling proteins in health and disease Maintaining normal bone structure and strength depends on a group of signaling proteins called cytokines that bind to receptor molecules on cell surfaces. Natalie Sims at St. Vincent’s Institute of Medical Research and The University of Melbourne in Australia reviews the role of cytokines in a specific signaling pathway in bone development and disease. Two of the proteins in this pathway respond to cytokine activity, whereas the third inhibits the cytokines’ effects. Studies in mice and humans have identified links between specific bone defects and spontaneous or experimentally induced mutations in the genes that code for the three proteins. The review covers the significance of recent findings to several types of cells that form new bone, degrade bone as part of normal bone turnover, and sustain the structure of bone and cartilage.