JAK2 inhibition with baricitinib stunts growth and postnatal development in juvenile rats

The Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway has recently emerged as an important regulator of musculoskeletal development. Inhibition of the pathway with small-molecule JAK inhibitors (jakinibs) may improve tendon development and healing. The goal of the present study was to characterize the effects of blocking JAK1 and 2 during a key postnatal musculoskeletal growth phase in Sprague-Dawley rats (postnatal day (PND) 7-28). We administered vehicle or baricitinib via chow (3 mg, or 10 mg/kg BW/day), which blocks JAK1 and JAK2, for 21 days and characterized the resulting systemic and musculoskeletal effects. We found a striking reduction in overall growth of the juvenile rats with baricitinib treatment, with a reduction in body weight of ∼30% for males and ∼20% for females at PND 28. The spleen was smaller in size with baricitinib treatment, even after normalization to body weight. Bone and tendon similarly showed decreases in mechanical properties without dramatic changes in material properties. Consistent with the role of JAK2 in growth hormone signaling, circulating IGF-1 levels were ∼65% lower in animals fed baricitinib. Our findings suggest that oral administration of baricitinib impairs postnatal growth and development in juvenile rats, likely through the GH/JAK2/IGF-1 axis. The clinical translation of these preclinical data and potential for similar adverse clinical effects of baricitinib in pediatric subjects is unknown. Baricitinib could provide effective treatment for acromegaly, but clinicians should be cautioned of this potential side effect and strongly consider using alternative treatments in children who have yet to reach full size.