JAK inhibition increases bone mass in steady-state conditions and ameliorates pathological bone loss by stimulating osteoblast function

Abstract

Janus kinase (JAK)–mediated cytokine signaling has emerged as an important therapeutic target for the treatment of inflammatory diseases such as rheumatoid arthritis (RA). Accordingly, JAK inhibitors compose a new class of drugs, among which tofacitinib and baricitinib have been approved for the treatment of RA. Periarticular bone erosions contribute considerably to the pathogenesis of RA. However, although the immunomodulatory aspect of JAK inhibition (JAKi) is well defined, the current knowledge of how JAKi influences bone homeostasis is limited. Here, we assessed the effects of the JAK inhibitors tofacitinib and baricitinib on bone phenotype (i) in mice during steady-state conditions or in mice with bone loss induced by (ii) estrogen-deficiency (ovariectomy) or (iii) inflammation (arthritis) to evaluate whether effects of JAKi on bone metabolism require noninflammatory/inflammatory challenge. In all three models, JAKi increased bone mass, consistent with reducing the ratio of receptor activator of NF-κB ligand/osteoprotegerin in serum. In vitro, effects of tofacitinib and baricitinib on osteoclast and osteoblast differentiation were analyzed. JAKi significantly increased osteoblast function (P < 0.05) but showed no direct effects on osteoclasts. Additionally, mRNA sequencing and ingenuity pathway analyses were performed in osteoblasts exposed to JAKi and revealed robust up-regulation of markers for osteoblast function, such as osteocalcin and Wnt signaling. The anabolic effect of JAKi was illustrated by the stabilization of β-catenin. In humans with RA, JAKi induced bone-anabolic effects as evidenced by repair of arthritic bone erosions. Results support that JAKi is a potent therapeutic tool for increasing osteoblast function and bone formation.

Targeting actin-bundling protein L-plastin as an anabolic therapy for bone loss

“…Anti-sclerostin antibody is a new option for bone formation, and further clinical investigations are needed to evaluate its benefits and risks (24). In recent years, anabolic therapeutic strategies for pathological bone loss have attracted attention (25)(26)(27).…”

Safety of Janus Kinase Inhibitors in Older Patients: A Focus on the Thromboembolic Risk

“…At the same time, the improved selectivity of these agents may shed light on a refined appreciation for safe use of these agents [6]. Finally, as new uses for this class of drugs are uncovered, such as in the fight against osteoporosis, it is increasingly likely that geriatricians will find themselves at the forefront of prescribing and monitoring their use [48].…”

Impact of Janus Kinase Inhibition on the Treatment of Axial Spondyloarthropathies

“…With regard to the effects of JAKinib on bone metabolism, an important aspect in SpA, an experimental JAK2 inhibitor, AG490, reduced alkaline phosphatase activity in primary bonederived cells from AS patients and healthy controls (25). On the other hand, tofacitinib and baricitinib increased bone mass in the K/BxN serum-transfer mouse model of RA-like arthritis and enhanced osteoblast function in vitro while sparing osteoclasts (26). These findings were confirmed in two RA patients treated with tofacitinib showing a substantial reduction in erosions of the metacarpophalangeal joints by micro-CT. Because activation of bone formation is deleterious in axSpA but useful in RA, further insight into the differential effects of JAKinib in these diseases is warranted.…”

“…Reactivation of hepatitis B has been reported with JAKinib treatment, but treatment with tofacitinib in refractory cases under antiviral prophylaxis seems safe and effective (60,61). The increased incidence of HZ is specific for JAKinib treatment and, for unknown reasons, seems to be more pronounced in Japan and Korea, ranging from 3.3 to 3.9 per 100 patient-years (26,57,58,62,63). The common risk factor for HZ over the different JAKinib was age (64,65).…”