ABSTRACT
BACKGROUND: The types of bone damage in rheumatoid arthritis (RA) include joint erosion, periarticular osteoporosis, and systemic osteoporosis. Janus kinase (JAK) inhibitors ameliorate inflammation and joint erosion in RA, but their effect on the three types of bone loss have not been reportedly explored in depth. We aimed to clarify how JAK inhibitors influence the various types of bone loss in arthritis by modulating osteoclastic bone resorption and/or osteoblastic bone formation. METHODS: Collagen-induced arthritis (CIA) mice were treated with a JAK inhibitor after the onset of arthritis. Micro-computed tomography (µCT) and histological analyses (bone morphometric analyses) on the erosive calcaneocuboid joint, periarticular bone (distal femur or proximal tibia), and vertebrae were performed. The effect of four different JAK inhibitors on osteoclastogenesis under various conditions was examined in vitro. RESULTS: The JAK inhibitor ameliorated joint erosion, periarticular osteopenia and systemic bone loss. It reduced the osteoclast number in all the three types of bone damage. The JAK inhibitor enhanced osteoblastic bone formation in the calcaneus distal to inflammatory synovium in the calcaneocuboid joints, periarticular region of the tibia and vertebrae, but not the inflamed calcaneocuboid joint. All the JAK inhibitors suppressed osteoclastogenesis in vitro to a similar extent in the presence of osteoblastic cells. Most of the JAK inhibitors abrogated the suppressive effect of Th1 cells on osteoclastogenesis by inhibiting IFN-γ signaling in osteoclast precursor cells, while a JAK inhibitor did not affect this effect due to less ability to inhibit IFN-γ signaling. CONCLUSIONS: The JAK inhibitor suppressed joint erosion mainly by inhibiting osteoclastogenesis, while it ameliorated periarticular osteopenia and systemic bone loss by both inhibiting osteoclastogenesis and promoting osteoblastogenesis. These results indicate that the effect of JAK inhibitors on osteoclastogenesis and osteoblastogenesis depends on the bone damage type and the affected bone area. In vitro studies suggest that while JAK inhibitors inhibit osteoclastic bone resorption, their effects on osteoclastogenesis in inflammatory environments vary depending on the cytokine milieu, JAK selectivity and cytokine signaling specificity. The findings reported here should contribute to the strategic use of antirheumatic drugs against structural damages in RA.
ABSTRACT
Osteoarthritis (OA), in which M1 macrophage polarization in the synovium exacerbates disease progression, is a major cause of cartilage degeneration and functional disabilities. Therapeutic strategies of OA designed to interfere with the polarization of macrophages have rarely been reported. Here, we report that SHP099, as an allosteric inhibitor of src-homology 2-containing protein tyrosine phosphatase 2 (SHP2), attenuated osteoarthritis progression by inhibiting M1 macrophage polarization. We demonstrated that M1 macrophage polarization was accompanied by the overexpression of SHP2 in the synovial tissues of OA patients and OA model mice. Compared to wild-type (WT) mice, myeloid lineage conditional Shp2 knockout (cKO) mice showed decreased M1 macrophage polarization and attenuated severity of synovitis, an elevated expression of cartilage phenotype protein collagen II (COL2), and a decreased expression of cartilage degradation markers collagen X (COL10) and matrix metalloproteinase 3 (MMP3) in OA cartilage. Further mechanistic analysis showed thatSHP099 inhibited lipopolysaccharide (LPS)-induced Toll-like receptor (TLR) signaling mediated by nuclear factor kappa B (NF-κB) and PI3K-AKT signaling. Moreover, intra-articular injection of SHP099 also significantly attenuated OA progression, including joint synovitis and cartilage damage. These results indicated that allosteric inhibition of SHP2 might be a promising therapeutic strategy for the treatment of OA.
