The alarmin S100A9 hampers osteoclast differentiation from human circulating precursors by reducing the expression of RANK

Abstract

The alarmin S100A8/A9 is implicated in sterile inflammation‐induced bone resorption and has been shown to increase the bone‐resorptive capacity of mature osteoclasts. Here, we investigated the effects of S100A9 on osteoclast differentiation from human CD14+ circulating precursors. Hereto, human CD14+ monocytes were isolated and differentiated toward osteoclasts with M‐CSF and receptor activator of NF‐κB (RANK) ligand (RANKL) in the presence or absence of S100A9. Tartrate‐resistant acid phosphatase staining showed that exposure to S100A9 during monocyte‐to‐osteoclast differentiation strongly decreased the numbers of multinucleated osteoclasts. This was underlined by a decreased resorption of a hydroxyapatite‐like coating. The thus differentiated cells showed a high mRNA and protein production of proinflammatory factors after 16 h of exposure. In contrast, at d 4, the cells showed a decreased production of the osteoclast‐promoting protein TNF‐α. Interestingly, S100A9 exposure during the first 16 h of culture only was sufficient to reduce osteoclastogenesis. Using fluorescently labeled RANKL, we showed that, within this time frame, S100A9 inhibited the M‐CSF‐mediated induction of RANK. Chromatin immunoprecipitation showed that this was associated with changes in various histone marks at the epigenetic level. This S100A9‐induced reduction in RANK was in part recovered by blocking TNF‐α but not IL‐1. Together, our data show that S100A9 impedes monocyte‐to‐osteoclast differentiation, probably via a reduction in RANK expression.—Di Ceglie, I., Blom, A. B., Davar, R., Logie, C., Martens, J. H. A., Habibi, E., Böttcher, L.‐M., Roth, J., Vogl, T., Goodyear, C. S., van der Kraan, P. M., van Lent, P. L., van den Bosch, M. H. The alarmin S100A9 hampers osteoclast differentiation from human circulating precursors by reducing the expression of RANK. FASEB J. 33, 10104–10115 (2019). http://www.fasebj.org

Baseline serum biomarkers of inflammation, bone turnover and adipokines predict spinal radiographic progression in ankylosing spondylitis patients on TNF inhibitor therapy

“…Furthermore, higher fecal calprotectin levels at baseline were reported to predict treatment response to adalimumab [32]. It is known that calprotectin subunits s100A8 and A9 have an effect on osteoclasts and osteoblasts, both seem to be involved during differentiation of osteocytes: Whilst s100A8 is suggested to play a stimulating role in osteoblast differentiation, S100A9 seems to hamper differentiation of osteoclasts [33,34]. Interestingly, calprotectin serum levels were not associated with the clinical presence or activity of concomitant inflammatory bowel disease in our cohort.…”

Plumbagin, a Biomolecule with (Anti)Osteoclastic Properties

“…Although RANKL and M-CSF are usually described as the critical factors that determine if osteoclast differentiation takes place, the expression of the receptor RANK is also of importance. A couple of recent publications highlight the fact that the regulation of RANK expression is an effective means to change the effectiveness of osteoclast differentiation [37][38][39]. Indeed, RANK expression on macrophages is quite low and it is therefore not surprising that RANK abundance can be a limiting factor in osteoclastogenesis.…”

“…Indeed, RANK expression on macrophages is quite low and it is therefore not surprising that RANK abundance can be a limiting factor in osteoclastogenesis. For example, di Ceglie et al recently (2019) described that the endogenous DAMP and marker for sterile inflammation in rheumatoid arthritis, the alarmin S100A9, reduced M-CSF-induced RANK expression to limit osteoclastogenesis [39].…”

Macrophage-Derived Extracellular Vesicles as Carriers of Alarmins and Their Potential Involvement in Bone Homeostasis

“…Another study showed that S100A9 directly stimulates osteoclast formation from monocytes in the context of osteomyelitis in the absence of RANKL (75). However, addition of S100A9 to human monocytes strongly inhibits osteoclast differentiation (76).…”