SHORT CHAIN FATTY ACIDS MITIGATE OSTEOCLAST-MEDIATED ARTHRITIC BONE REMODELLING
Objective: To study the effects of Short Chain Fatty Acids (SCFAs) on arthritic bone remodeling.  Methods:  We treated a recently described preclinical murine model of psoriatic arthritis (PsA), R26STAT3Cstopfl/fl CD4Cre mice, with SCFA supplemented water. We also performed in vitro osteoclast differentiation assays in the presence of serum-level SCFAs to evaluate the direct impact of these microbial metabolites on maturation and function of osteoclasts. We further characterized the molecular mechanism of SCFAs by bulk transcriptomics analysis.  Results: The osteoporosis condition in R26STAT3Cstopfl/fl CD4Cre animals is attributed primarily to an expansion of osteoclast progenitor cells (OCPs), leading to robust osteoclast differentiation. We show that SCFA supplementation can rescue the osteoporosis phenotype in this model of PsA. Our in vitro experiments revealed an inhibitory effect of the SCFAs on osteoclast differentiation, even at very low serum concentrations. This suppression of osteoclast differentiation enabled SCFAs to impede osteoporosis development in R26STAT3Cstopfl/fl CD4Cre mice. Further interrogation revealed that bone marrow derived OCPs from diseased mice expressed a higher level of SCFA receptors than that of control mice and that the progenitor cells in the bone marrow of SCFA-treated mice presented a modified transcriptomic landscape, suggesting a direct impact by SCFAs on osteoclast progenitors.   Conclusion: We demonstrated how gut microbiota-derived SCFAs can regulate distal pathology, i.e., osteoporosis, and identified a potential therapeutic option for restoring bone density in rheumatic disease, further highlighting the critical role of the gut-bone axis in these disorders. Overall design: Control mice and R26STAT3Cstopfl/fl CD4Cre mice were either untreated or treated with SCFAs. At ~ 8 weeks their bone marrow was extracted and cultured for 24 hours. Non-adherent progenitor cells were collected for RNA extraction and bulk sequencing. We then compared differential gene expression across genotype and treatment.