Bone-fat linkage via interleukin-11 in response to mechanical loading

Positive regulators of bone formation, such as mechanical loading and PTH, stimulate and negative regulators, such as aging and glucocorticoid excess, suppress IL-11 gene transcription in osteoblastic cells. Signal transduction from mechanical loading and PTH stimulation involves two pathways: one is Ca2+-ERK-CREB pathway which facilitates binding of increment FosB/JunD to the AP-1 site to enhance IL-11 gene transcription, and the other is Smad1/5 phosphorylation that promotes IL-11 gene transcription via SBE binding and complex formation with increment FosB/JunD. The increased IL-11 suppresses Sost expression via IL-11R alpha-STAT1/3-HDAC4/5 pathway and enhances Wnt signaling in the bone to stimulate bone formation. Thus, IL-11 mediates stimulatory and inhibitory signals of bone formation by affecting Wnt signaling. Physiologically important stimulation of bone formation is exercise-induced mechanical loading, but exercise simultaneously requires energy source for muscle contraction. Exercise-induced stimulation of IL-11 expression in the bone increases the secretion of IL-11 from the bone. The increased circulating IL-11 acts like a hormone to enhance adipolysis as an energy source with a reduction in adipogenic differentiation via a suppression of Dkk1/2 expression in the adipose tissue. Such bone-fat linkage can be a mechanism whereby exercise increases bone mass and, at the same time, maintains energy supply from the adipose tissue.