Abstract
Background:
Osteitis on magnetic resonance imaging (MRI) and bone microstructure changes (BMC) on high-resolution peripheral quantitative computed tomography (CT) are the earliest signs of arthritis, preceding the development of bone erosion on X-ray in rheumatoid arthritis (RA). Recently, a Janus kinase (JAK) inhibitor, baricitinib, reportedly suppresses these early changes. This study aimed to elucidate the underlying molecular mechanism of osteitis and BMC using an animal model of RA and human samples.
Methods:
Osteitis and BMCs were assessed via MRI and micro-CT, respectively, in zymosan-treated SKG mice. Bone marrow (BM) cells were analysed via flow cytometry. JAK‒signal transducer and activator of transcription (STAT) cytokine expression was measured via performing quantitative PCR. Zymosan-treated SKG mice received baricitinib, anti-granulocyte‒macrophage colony-stimulating factor (GM-CSF) antibodies, or recombinant GM-CSF (r-GM-CSF). r-GM-CSF was also used in an in vitro osteoclast differentiation assay. Osteoclast differentiation was also investigated with human monocytes.
Results:
Osteitis and BMCs occurred prior to arthritis in SKG mice. Granulocyte‒macrophage-lineage cells and osteoclast precursor cells (OCPs) expanded in the inflammatory BM. Receptor activator of nuclear factor kappa-B ligand-positive osteoclasts were observed at BMC sites. The expression of GM-CSF, a JAK‒STAT cytokine, was upregulated in osteitic BM. Both baricitinib and anti-GM-CSF antibodies suppressed osteitis and BMCs, whereas r-GM-CSF exacerbated these changes. In vitro addition of r-GM-CSF to osteoclast differentiation assay markedly increased the number and size of osteoclasts, especially when added in the late phase of osteoclast differentiation both in mice and humans.
Conclusions:
GM-CSF drives osteitis and BMCs by increasing granulocyte‒macrophage-lineage cells and OCPs and promoting osteoclast differentiation. Targeting GM-CSF is a potential therapeutic strategy to prevent early radiographic changes in RA.