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

Area of Science:

• Bone Biology
• Endocrinology
• Cell Signaling

Background:

• Bone homeostasis relies on endocrine and paracrine factors, including cytokines.
• Inflammatory conditions can alter local and systemic cytokine levels, impacting bone.
• The Janus kinase-STAT (JAK-STAT) signaling pathway plays a key role in mediating these effects.

Purpose of the Study:

• To review bone-active cytokines that initiate JAK-STAT signaling.
• To outline skeletal defects associated with modifications in the JAK-STAT pathway.
• To describe defects in JAK1, STAT3, and SOCS3 signaling in mouse models and humans.

Main Methods:

• Review of studies on JAK-STAT signaling in bone.
• Analysis of mouse models with induced or spontaneous pathway modifications.
• Examination of human genetic data for JAK1, STAT3, and SOCS3 mutations.

Main Results:

• JAK-STAT pathway activation indirectly stimulates osteoclast formation via JAK1 and STAT3 in accessory cells.
• Osteoblast differentiation increases secondary to osteoclast formation through IL-6-dependent pathways.
• STAT3 signaling in growth plate chondrocytes and osteocytes is essential for bone lengthening and formation, respectively.

Conclusions:

• STAT3 signaling is vital for normal bone lengthening and formation.
• SOCS3 (suppressor of cytokine signaling 3) is necessary to suppress IL-6/gp130 cytokine activity for cortical bone formation.
• Dysregulation of JAK-STAT signaling contributes to skeletal defects.