Reduced estrogen signaling contributes to bone loss and cardiac dysfunction in interleukin‐10 knockout mice

Abstract

Characterization of the interleukin (IL)‐10 knockout (KO) mouse with chronic gut inflammation, cardiovascular dysfunction, and bone loss suggests a critical role for this cytokine in interorgan communication within the gut, bone, and cardiovascular axis. We sought to understand the role of IL‐10 in the cross‐talk between these systems. Six‐week‐old IL‐10 KO mice and their wild type (WT) counterparts were maintained on a standard rodent diet for 3 or 6 months. Gene expression of proinflammatory markers and Fgf23, serum 17β‐estradiol (E2), and cardiac protein expression were assessed. Ileal Il17a and Tnf mRNA increased while Il6 mRNA increased in the bone and heart by at least 2‐fold in IL‐10 KO mice. Bone Dmp1 and Phex mRNA were repressed at 6 months in IL‐10 KO mice, resulting in increased Fgf23 mRNA (~4‐fold) that contributed to increased fibrosis. In the IL‐10 KO mice, gut bacterial β‐glucuronidase activity and ovarian Cyp19a1 mRNA were lower (p < 0.05), consistent with reduced serum E2 and reduced cardiac pNOS3 (Ser1119) in these mice. Treatment of ileal lymphocytes with E2 reduced gut inflammation in WT but not IL‐10 KO mice. In conclusion, our data suggest that diminished estrogen and defective bone mineralization increased FGF23 which contributed to cardiac fibrosis in the IL‐10 KO mouse.

Pyroptosis mediates osteoporosis via the inflammation immune microenvironment

“…Inflammatory factors, including IL-1, IL-6, IL-17, and TNF-α, alongside osteoprotegerin (OPG) produced by T lymphocytes, B lymphocytes, macrophages, and dendritic cells, are included among the target genes of the estrogen receptor ( 7 ). IL-10 knockout mice develop osteoporosis and have significantly increased expression of the inflammatory factors IL-6 and TNF in bone, and treatment with E2 ameliorates this process, suggesting that the development of inflammation in bone is closely linked to estrogen deficiency ( 14 ). Estrogen inhibits osteoclast differentiation by impeding RANKL/M-CSF-induced activator protein 1 (AP-1) transcription ( 15 ).…”