Abstract
Despite knowledge the gut microbiota regulates bone mass, mechanisms governing the normal gut microbiota’s osteoimmunomodulatory effects on skeletal remodeling and homeostasis are unclear in the healthy adult skeleton. Young adult specific-pathogen-free and germ-free mice were used to delineate the commensal microbiota’s immunoregulatory effects on osteoblastogenesis, osteoclastogenesis, marrow T-cell hematopoiesis, and extra-skeletal endocrine organ function. We report the commensal microbiota has anti-anabolic effects suppressing osteoblastogenesis and pro-catabolic effects enhancing osteoclastogenesis, which drive bone loss in health. Suppression of Sp7(Osterix) and Igf1 in bone, and serum IGF1, in specific-pathogen-free mice suggest the commensal microbiota’s anti-osteoblastic actions are mediated via local disruption of IGF1-signaling. Differences in the RANKL/OPG Axis in vivo, and RANKL-induced maturation of osteoclast-precursors in vitro, indicate the commensal microbiota induces sustained changes in RANKL-mediated osteoclastogenesis. Candidate mechanisms mediating commensal microbiota’s pro-osteoclastic actions include altered marrow effector CD4+T-cells and a novel Gut-Liver-Bone Axis. The previously unidentified Gut-Liver-Bone Axis intriguingly implies the normal gut microbiota’s osteoimmunomodulatory actions are partly mediated via immunostimulatory effects in the liver. The molecular underpinnings defining commensal gut microbiota immunomodulatory actions on physiologic bone remodeling are highly relevant in advancing the understanding of normal osteoimmunological processes, having implications for the prevention of skeletal deterioration in health and disease.
Highlights
Homeostasis occurs when balanced osteoclast-osteoblast actions remodel the adult skeleton, and there is no net gain/loss of osseous tissue[12,13,14, 18]
Subsequent GF mouse model investigations demonstrating that the normal gut microbiota supports skeletal growth and bone formation in BALB/c22 and CB6F123 mice, notably imply that the commensal microbiota impact on skeletal physiology is regulated by mouse strain genetic determinants
While resident gut microbes have been reported to have pro-osteoclastic immunomodulatory effects impairing the accrual of bone mass in growing C57BL/6 mice[21], and pro-anabolic actions enhancing liver IGF1 mediated skeletal growth in BALB/c22 and CB6F123 mice, the normal gut microbiota’s osteoimmunomodulatory effects on skeletal physiology are largely unknown in the healthy adult skeleton
Summary
Homeostasis occurs when balanced osteoclast-osteoblast actions remodel the adult skeleton, and there is no net gain/loss of osseous tissue[12,13,14, 18]. While resident gut microbes have been reported to have pro-osteoclastic immunomodulatory effects impairing the accrual of bone mass in growing C57BL/6 mice[21], and pro-anabolic actions enhancing liver IGF1 mediated skeletal growth in BALB/c22 and CB6F123 mice, the normal gut microbiota’s osteoimmunomodulatory effects on skeletal physiology are largely unknown in the healthy adult skeleton. This osteoimmunology study in young adult C57BL/6 SPF vs GF mice introduces the commensal gut microbiota as a potent immunoregulator of osteoclast-osteoblast mediated bone remodeling processes in the healthy adult skeleton. This investigation highlights the commensal gut microbiota as a critical regulator of physiologic tissue remodeling and homeostasis at extra-gastrointestinal sites[11], a biological phenomenon which is currently unappreciated and not well understood
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