JAK/STAT as a Potential Therapeutic Target for Osteolytic Diseases

Abstract

Several cytokines with major biological functions in inflammatory diseases exert their functions through the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signal transduction pathway. JAKs phosphorylate the cytoplasmic domain of the receptor, inducing the activation of its substrates, mainly the proteins known as STATs. STATs bind to these phosphorylated tyrosine residues and translocate from the cytoplasm to the nucleus, further regulating the transcription of several genes that regulate the inflammatory response. The JAK/STAT signaling pathway plays a critical role in the pathogenesis of inflammatory diseases. There is also increasing evidence indicating that the persistent activation of the JAK/STAT signaling pathway is related to several inflammatory bone (osteolytic) diseases. However, the specific mechanism remains to be clarified. JAK/STAT signaling pathway inhibitors have gained major scientific interest to explore their potential in the prevention of the destruction of mineralized tissues in osteolytic diseases. Here, our review highlights the importance of the JAK/STAT signaling pathway in inflammation-induced bone resorption and presents the results of clinical studies and experimental models of JAK inhibitors in osteolytic diseases.

Keywords: JAK/STAT inhibitor; JAK/STAT signaling pathway; cytokines; osteoblasts; osteoclasts; osteolysis; osteolytic disease.

Figure 1

Potential mechanisms for activation of the JAK-STAT signaling pathway. Once the cytokines bind to their receptors with intracellular signaling via Janus kinase, it triggers an intracellular signal transducer that causes the autophosphorylation and phosphorylation of the cytoplasmic domain of cytokine receptors associated with JAKs (JAK1, JAK2, JAK3, and TYK2) and also triggers the phosphorylation of the STAT proteins. JAK-mediated STAT phosphorylation results in the phosphorylation and dimerization of STAT protein, nuclear translocation, and induction of transcription of inflammatory cytokines such as interleukins (IL)-1, IL-6, IL-15, tumor necrosis factor alpha (TNF-α), and interferons (IFN).

Figure 2

The recognition of microbial components (molecular patterns associated with pathogens—PAMPs) by defense cells induces an increase in inflammatory cytokines in periodontal tissues. These cytokines stimulate the activation of the JAK-STAT pathway, which results in the transduction of more inflammatory cytokines, amplifying the inflammatory response and tissue destruction. JAK inhibitors bind to and competitively inhibit the kinase domain of JAKs, thereby preventing JAKs from phosphorylating STATs and other substrates so that intracellular signals cannot be further transduced. Because JAKs are critical for multiple different cytokines, JAK inhibitors can block the action of a range of cytokines and contribute to the reduction of the inflammatory response and tissue destruction in the periodontium.