Targeting inflammatory osteoclasts with probiotic yeast S. boulardii reduces bone loss in osteoporosis. ORIOS_OCL_Probiotics

Bone destruction is a hallmark of chronic inflammation, and osteoclasts arising in these pathological conditions differ in their origin and immune function from steady state ones. However, their phenotype and the mechanisms controlling their development and function are still poorly understood. Here, transcriptomic profiling on osteoclasts derived from monocytes (MN-OCLs) and dendritic cells (DC-OCLs) representing steady-state and inflammatory osteoclasts, respectively, revealed differences in functional and molecular pathways associated with host immune responses. This analysis also revealed an upregulation in DC-OCLs of the osteoclastogenic costimulatory Ig-like-dependent pathway and the pattern-recognition receptor pathway including TLR2, Dectin-1 and Mincle. Agonizing these receptors in vitro specifically blocked osteoclast differentiation from DCs and ovariectomized (OVX) mice, but not from monocytes and SHAM control mice. Osteoporosis is linked to microbiota dysbiosis and TLR2, Dectin-1 and Mincle are major receptors for recognition of commensal and pathogenic fungi. We demonstrated that medium conditioned by the yeast probiotic Saccharomyces boulardi CNCM I-745 (Sb) dramatically inhibited osteoclastogenesis from dendritic cells without major impact on MN-OCLs. In vivo, treatment with Sb reduced bone destruction in OVX mice, without affecting bone density in control mice. These findings showed for the first time a preferential use of the costimulatory pathway by osteoclasts associated with bone destruction, which enable specific blocking of their differentiation. Our results highlight the protective effect of yeast probiotics on bone destruction and provides novel regulatory mechanisms and new therapeutic targets for inflammatory bone loss.