JAK/STAT Activation: A General Mechanism for Bone Development, Homeostasis, and Regeneration

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.

Keywords: JAK/STAT; bone development; homeostasis; osteoblast; osteoclast; osteoporosis.

Figure 1

Janus tyrosine kinase (JAK)/signal transducers and activators of transcription (STAT) signaling in bone homeostasis [1,2,3,4,6,7,8,9,10,11,12,13,14,15,16,17]. Figure contains graphics from Servier Medical Art, licensed under a Creative Common Attribution 3.0 Generic License. http://smart.servier.com/.

Figure 2

JAK/STAT pathway at a glance. (A) Cytokines interact with their corresponding receptor, which, after oligomerization, activates JAK and initiates JAK-mediated phosphorylation of its own cytoplasmic domain. Receptor phosphorylation causes STAT binding in close proximity to JAK that in turn mediates tyrosine-phosphorylation (p-Tyr) of the latter. STAT phosphorylation results in dimerization, nuclear translocation, DNA binding, and modulation of gene transcription. (I) All STAT can bind to interferon-γ (IFN-γ)-activated sequence (GAS) DNA motifs while (II) only STAT2 after forming a trimeric complex of STAT1–STAT2–IRF9 engages Interferon-stimulated Response Element (ISRE) DNA binding. (B) Four domains of JAK facilitate interaction with upstream receptors and promotion of kinase function (FERM domain), interaction with upstream receptors (SH2-like domain), control of kinase activity (pseudokinase domain), and trans-activation and tyrosine-phosphorylation of receptors, JAKs and STATs (kinase domain). The seven domains of STAT facilitate protein-protein interactions (N-terminal domain), protein–protein interactions and nuclear-localization (coiled-coil domain), nuclear import, DNA binding, and transcriptional activity (DNA-binding domain), structural organization and transcriptional activity (linker domain), dimerization and interaction with upstream receptors (SH2 domain), canonical signaling (transactivation domain), canonical and non-canonical functions (C-terminal domain).