JAK Inhibition Increases Bone Mass in Steady state Conditions and Ameliorates Pathological Bone Loss by Stimulating Osteoblast Function

Sci Transl Med 2020;12(530):pii: eaay4447

JAKi significantly increased osteoblast function but showed no direct effects on osteoclasts.JAK signalling has emerged as an important therapeutic target for inflammatory disease, and the immunomodulation of JAK inhibition is well defined. Less well understood is the influence of this new class of drugs on bone homeostasis. This is important, as cytokine dysregulation triggers bone loss, and periarticular erosions contribute to the pathogenesis of RA. This study investigated the effect of BARI and TOF in murine and human models of bone loss. Mice were randomly assigned to one of three experimental groups to study either stead-state conditions, non-inflammatory or inflammatory bone loss. Human samples were also used to look for signs of bone repair. In all three mouse models, JAK inhibition increased tibial trabecular mass, a finding possibly explained by a significant reduction in the RANKL/OPG ratio – suggesting a systemic osteoanabolic effect. Osteoblast function was also increased with the use of JAKi, but there was no direct effect on osteoclast differentiation. In human patients with RA, JAKi agents repaired arthritic bone lesions, hinting at a bone-anabolic effect. This study suggests that the JAK inhibitors are a potent therapeutic tool for increasing osteoblast function and bone formation.