A Liver-Bone Endocrine Relay by IGFBP1 Promotes Osteoclastogenesis and Mediates FGF21-Induced Bone Resorption

Abstract

SUMMARY Fibroblast growth factor 21 (FGF21) promotes insulin sensitivity but causes bone loss. It elevates bone resorption by an undefined non-osteoclast-autonomous mechanism. We have detected a pro-osteoclastogenic activity in the hepatic secretome that is increased by FGF21, and largely attributed to insulin-like growth factor binding protein 1 (IGFBP1). Ex vivo osteoclast differentiation and in vivo bone resorption are both enhanced by recombinant IGFBP1 but suppressed by an IGFBP1-blocking antibody. Anti-IGFBP1 treatment attenuates ovariectomy-induced osteoporosis, and abolishes FGF21-induced bone loss while maintaining its insulin-sensitizing metabolic benefit. Mechanistically, IGFBP1 functions via its RGD domain to bind to its receptor integrin β1 on osteoclast precursors, thereby potentiating RANKL-stimulated Erk-phosphorylation and NFATc1 activation. Consequently, osteoclastic integrin β1 deletion confers resistance to the resorption-enhancing effects of both IGFBP1 and FGF21. Therefore, the hepatokine IGFBP1 is a critical liver-bone hormonal relay that promotes osteoclastogenesis and bone resorption, as well as an essential mediator of FGF21-induced bone loss.

FGF21 gene therapy as treatment for obesity and insulin resistance

“…Pharmacological treatment with FGF21 or transgenic overexpression has been associated with perturbation of bone homeostasis through increased bone resorption, which could cause bone loss (Wei et al , ; Wang et al , ; Talukdar et al , ; Charoenphandhu et al , ; Kim et al , ). Given the therapeutic potential of AAV8‐hAAT‐FGF21 for the treatment of obesity and diabetes, we evaluated the long‐term effects of gene transfer on the bones of the animals treated with the highest dose of vector.…”

“…The pathological effects of FGF21 have been reported to be mediated, at least in part, by increased production of insulin‐like growth factor binding protein 1 (IGFPB1) by the liver (Wang et al , ). In agreement with the lack of bone alterations, high‐dose AAV8‐hAAT‐FGF21 treatment did not lead to an increase in the levels of circulating IGFBP1 protein in animals treated 12 (young adults) or 6 (adults) months earlier when compared to null‐injected HFD‐fed mice (Fig EV3P).…”

Loss of Hepatic Mitochondrial Long-Chain Fatty Acid Oxidation Confers Resistance to Diet-Induced Obesity and Glucose Intolerance

“…This was reflected in an increase in serum levels of Igfbp1, Gdf15 and Fgf21, suggesting that these hepatokines are contributing to physiological adaptations in response to a loss of mitochondrial fatty acid oxidation (Figure 3D). Due to the reported role of Igfbp1 and Fgf21 in bone we measured aspects of bone quality (Wang et al, 2015). The increase in these hepatokines did not affect long bone growth (Figure 1A, 1B) or bone structure (Figure S3).…”

Altered bone‐regulating myokine expression in skeletal muscle Of Duchenne muscular dystrophy mouse models

“…Considering the broad metabolic manifestations in DMD, and the diverse effects of FGF21 on energy metabolism, further studies to elucidate the pathological roles of muscle‐derived FGF21 in DMD are warranted. Moreover, in addition to its metabolic functions, it has been speculated that FGF21 negatively regulates bone homeostasis by stimulating adipogenesis and inhibiting osteogenesis from BMSCs, and indirectly promote osteoclastogenesis by means of stimulating expression of insulin‐like growth factor‐binding protein 1 (IGFBP1) from liver . The prospect of elevated FGF21 in dystrophic muscle acting remotely on bone and causing a low bone mass phenotype deserves further investigation.…”