Abstract
The Janus kinase (JAK) signal transducer and activator of transcription (STAT) signaling pathway serves as an important downstream mediator for a variety of cytokines, hormones, and growth factors. Emerging evidence suggests JAK/STAT signaling pathway plays an important role in bone development, metabolism, and healing. In this light, pro-inflammatory cytokines are now clearly implicated in these processes as they can perturb normal bone remodeling through their action on osteoclasts and osteoblasts at both intra- and extra-articular skeletal sites. Here, we summarize the role of JAK/STAT pathway on development, homeostasis, and regeneration based on skeletal phenotype of individual JAK and STAT gene knockout models and selective inhibition of components of the JAK/STAT signaling including influences of JAK inhibition in osteoclasts, osteoblasts, and osteocytes.
Highlights
The sense of and reaction to external signals from the environment is essential for the survival of every living system
Cytokine-mediated activation of Janus tyrosine kinase (JAK)/signal transducers and activators of transcription (STAT) signaling tightly regulates bone development, bone homeostasis, and bone regeneration leading to normal bone structure and strength
Disturbing the tight regulation during local or systemic inflammation as observed in the pathogenesis of inflammatory diseases leads to bone erosions, osteoporosis, and bone healing disorders
Summary
The sense of and reaction to external signals from the environment is essential for the survival of every living system. External signals are primarily sensed and processed by biochemical receptors in the cell membrane and transmitted via signaling pathways and cascades that form a network with a variety of other pathways to further process the information These signals initiate mechanisms that are responsible for controlling phenotypic and functional outcomes, e.g., proliferation or apoptosis. Among these signal transduction pathways, the Janus tyrosine kinase (JAK)- and signal transducers and activators of transcription (STAT)-mediated signaling are responsible for transducing signals of more than fifty cytokines, growth factors and hormones, regulated on multiple levels [1,2,3]. STAT binding can be observed proximal to DNA responsive elements and distal and far from protein-encoding genes [2] These sites can be distinguished in majority as enhancers, epigenetic hotspots, and non-coding loci. All the different modes of action and the various combinations of JAK and STAT proteins make an investigation on their targets almost impossible
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