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JAK inhibition increases bone mass in steady-state conditions and ameliorates pathological bone loss by stimulating
Susanne Adam1,2, Nils Simon1,2, Ulrike Steffen1,2
1Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Department of Internal Medicine 3-Rheumatology and Immunology, Universitätsklinikum Erlangen, Erlangen, Germany.
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.
Insights
Janus kinase inhibitors (JAKi) promote bone formation and increase bone mass in models of steady-state, estrogen-deficiency, and inflammatory bone loss. JAKi enhance osteoblast function, offering a therapeutic strategy for bone health.
Area of Science:
- Immunology
- Rheumatology
- Bone Biology
Background:
- Janus kinase (JAK)-mediated cytokine signaling is a therapeutic target for inflammatory diseases like rheumatoid arthritis (RA).
- JAK inhibitors (JAKi), including tofacitinib and baricitinib, are approved for RA treatment.
- The impact of JAKi on bone homeostasis, particularly in the context of periarticular bone erosions in RA, is not fully understood.
Purpose of the Study:
- To investigate the effects of JAK inhibitors (tofacitinib and baricitinib) on bone phenotype.
- To determine if JAKi's effects on bone metabolism are dependent on inflammatory or non-inflammatory challenges.
- To evaluate JAKi's influence on bone loss induced by estrogen deficiency and arthritis.
Main Methods:
- Assessment of bone phenotype in mice under steady-state, estrogen-deficiency (ovariectomy), and inflammatory (arthritis) conditions.
- In vitro analysis of osteoclast and osteoblast differentiation in response to JAK inhibitors.
- mRNA sequencing and Ingenuity Pathway Analysis in osteoblasts treated with JAKi.
- Evaluation of bone erosion repair in human RA patients treated with JAKi.
Main Results:
- JAK inhibitors increased bone mass in all three mouse models (steady-state, ovariectomy, arthritis).
- JAKi treatment reduced the receptor activator of NF-κB ligand/osteoprotegerin ratio.
- In vitro, JAKi significantly enhanced osteoblast function without direct effects on osteoclasts.
- JAKi upregulated osteoblast markers, including osteocalcin and Wnt signaling, stabilizing β-catenin.
- Human RA patients treated with JAKi showed repair of arthritic bone erosions.
Conclusions:
- JAK inhibitors exert bone-anabolic effects, increasing osteoblast function and bone formation.
- These findings suggest JAKi are potent therapeutic tools for enhancing bone mass and potentially treating bone loss associated with inflammatory conditions.
- The bone-anabolic effects of JAKi are evident in both inflammatory and non-inflammatory settings.
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