New York University Langone Health, New York City.
New York University School of Medicine, New York City.
Arthritis Rheumatol. 2024 Apr;76(4):647-659. doi: 10.1002/art.42765. Epub 2024 Feb 18.
The objective for this study was to evaluate the effects of short chain fatty acids (SCFAs) on arthritic bone remodeling.
We treated a recently described preclinical murine model of psoriatic arthritis (PsA), R26STAT3C 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 transcriptional analysis.
The osteoporosis condition in R26STAT3C CD4Cre animals is attributed primarily to robust osteoclast differentiation driven by an expansion of osteoclast progenitor cells (OCPs), accompanied by impaired osteoblast development. 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 R26STAT3C CD4Cre mice. Further interrogation revealed that bone marrow-derived OCPs from diseased mice expressed a higher level of SCFA receptors than those 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 of SCFAs on bone marrow progenitors in the context of osteoporosis.
We demonstrated how gut microbiota-derived SCFAs can regulate distal pathology (ie, 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.
本研究旨在评估短链脂肪酸（SCFAs）对关节炎性骨重塑的影响。
我们用富含 SCFA 的水治疗最近描述的银屑病关节炎（PsA）的临床前小鼠模型 R26STAT3C CD4Cre 小鼠。我们还在存在血清水平 SCFA 的情况下进行体外破骨细胞分化测定，以评估这些微生物代谢物对破骨细胞成熟和功能的直接影响。我们进一步通过转录分析来表征 SCFA 的分子机制。
R26STAT3C CD4Cre 动物的骨质疏松症状况主要归因于破骨细胞祖细胞（OCP）的扩增所驱动的强大破骨细胞分化，同时伴有成骨细胞发育受损。我们表明，SCFA 补充可以挽救这种 PsA 模型中的骨质疏松症表型。我们的体外实验表明，SCFA 对破骨细胞分化具有抑制作用，即使在非常低的血清浓度下也是如此。这种对破骨细胞分化的抑制作用使 SCFAs 能够阻止 R26STAT3C CD4Cre 小鼠的骨质疏松症发展。进一步研究表明，来自患病小鼠的骨髓来源的 OCP 表达比对照小鼠更高水平的 SCFA 受体，并且 SCFA 处理小鼠的骨髓中的祖细胞呈现出修饰的转录组景观，表明 SCFAs 在骨质疏松症背景下直接影响骨髓祖细胞。
我们证明了肠道微生物群衍生的 SCFAs 如何调节远端病理学（即骨质疏松症），并确定了恢复风湿性疾病骨密度的潜在治疗选择，进一步强调了肠道-骨骼轴在这些疾病中的关键作用。
