Inhibitors of Janus kinases (JAKs), such as tofacitinib and baricitinib, are used to treat cytokine-mediated inflammatory diseases such as rheumatoid arthritis (RA). Some evidence has emerged to suggest a role for JAK signalling pathways in bone biology, but whether JAK inhibition affects bone remodelling has been uncertain. The results of a new study published in Science Translational Medicine shed light on exactly how JAK inhibitors affect bone in health and disease.

Credit: N. Smith/Springer Nature Limited

“We studied two patients with RA who received 5 mg tofacitinib twice daily,” states first author Susanne Adam. “High-resolution peripheral quantitative CT of their metacarpophalangeal joints revealed that tofacitinib treatment reduced bone erosions after 2 years by induction of bone formation.”

“Despite the constant progress in anti-rheumatic therapy options, restoring bone tissue that has been subjected to erosive damage by RA has not yet been achieved,” explains corresponding author Silke Frey. “Therefore, these findings were unprecedented and encouraged us to investigate the potential bone-anabolic effect of JAK inhibition.”

Interestingly, the authors found that 6 weeks of tofacitinib increased bone mass in healthy mice under homeostatic conditions. Both tofacitinib and baricitinib were able to increase trabecular thickness in ovariectomized mice (a model of post-menopausal osteoporosis) and to increase trabecular thickness and cortical thickness in mice with established K/B × N serum transfer-induced arthritis (a model of RA).

Delving deeper, the authors discovered that JAK inhibitors reduce bone loss by promoting new bone formation by osteoblasts, rather than by affecting osteoclasts. In vitro experiments and gene network analysis revealed a pathway in which JAK inhibition promotes the stabilization of β-catenin (an important part of the Wnt signalling pathway) and the expression of osteoanabolic genes such as OCN, which leads to an increase in the bone mineralization capacity of osteoblasts.

JAK inhibitors reduce bone loss by promoting new bone formation by osteoblasts

“The capability of JAK inhibitors to directly affect bone metabolism will expand their well-established role as anti-inflammatory agents,” says senior author Axel Hueber. “We expect JAK inhibition to not only ameliorate inflammation-induced bone damage, but also to provide additional value in treating osteoporosis-induced loss of bone density, which is a frequent comorbidity of RA.”