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

Abstract

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.

Fig. 1. Bone-active cytokines and receptor complexes that depend on SOCS3-negative feedback.

From left to right: a large number of cytokines form complexes with gp130. IL-6 and IL-11 bind to ligand-specific β-receptor subunits (IL-6R and IL-11R, respectively) to form complexes with glycoprotein 130 (gp130) homodimers. Oncostatin M (OSM) binds to its specific receptor (OSMR), which then recruits gp130 to form a heterodimer. The LIF (leukemia inhibitor factor) receptor is used by multiple cytokines. LIF itself signals through a complex containing the ligand bound to a heterodimer of LIF receptor (LIFR) and gp130. Cardiotrophin 1 (CT-1) also transduces signals through LIFR and gp130 and, potentially, a CT-1-specific receptor subunit that remains undefined. In addition to its ability to transduce signal through OSMR, OSM is also capable of signaling through a gp130:LIFR heterodimer. A subfamily of cytokines transduce signals through a complex containing gp130:LIFR and the ciliary neurotrophic factor (CNTF) receptor (CNTFR). The simplest complexes are formed by CNTF and neuropoietin (NP), but additional components are required for CLCF1 (Cardiotrophin-like cytokine factor 1) signaling. CLCF1 is secreted as a complex bound to either a soluble form of CNTFR or to cytokine receptor-like factor (CRLF). All receptors that bind gp130 activate predominantly JAK1 (although there are some that can bind JAK2 and TYK2), and once JAK1 is phosphorylated, STAT3, STAT1, and SHP2/Ras/MAPK signaling is activated. SHP2/Ras/MAPK signaling is mediated through tyrosine 757 (mouse) or 759 (human) in gp130. Each of these pathways is subject to negative feedback via SOCS3, which also depends on tyrosine 757/759. Two additional bone-active cytokines depend on SOCS3: granulocyte colony stimulating factor (G-CSF), which acts through a G-CSF receptor (G-CSFR) homodimer followed predominantly by JAK1 and STAT3 signaling, with negative feedback through SOCS3 and leptin, which acts through a leptin receptor (LepR) homodimer, followed by JAK2 and STAT5 signaling, which appears to also be suppressed by SOCS3.

Fig. 2. Context-dependent cytokine actions through gp130, JAK1, STAT3, and SOCS3 in bone formation and resorption.

a Inflammation during colitis, age-related bone loss, and rheumatoid arthritis leads to increased RANKL production by T cells or related inflammatory cells at sites of inflammation through JAK1 and STAT3. This indirect action increases osteoclast formation on the bone surface. b During cortical bone development, osteocytes respond to IL-6 family cytokines in the local environment, induce STAT3 signaling, and depend on SOCS3-negative feedback to prevent excessive osteoclast formation. c In the trabecular bone network, normal physiological production of IL-6 family cytokines promotes bone formation and requires feedback from SOCS3. Mechanical loading also induces bone formation through STAT3 signaling in osteocytes, but whether this is induction is dependent on gp130 or SOCS3-negative feedback is not yet known.