The endocrine hormone fibroblast growth factor 21 (FGF21) is a powerful modulator of glucose and lipid metabolism and a promising drug for type 2 diabetes. Here we identify FGF21 as a potent regulator of skeletal homeostasis. Both genetic and pharmacologic FGF21 gain of function lead to a striking decrease in bone mass. In contrast, FGF21 loss of function leads to a reciprocal high-bone-mass phenotype. Mechanistically, FGF21 inhibits osteoblastogenesis and stimulates adipogenesis from bone marrow mesenchymal stem cells by potentiating the activity of peroxisome proliferator-activated receptor γ (PPAR-γ). Consequently, FGF21 deletion prevents the deleterious bone loss side effect of the PPAR-γ agonist rosiglitazone. Therefore, FGF21 is a critical rheostat for bone turnover and a key integrator of bone and energy metabolism. These results reveal that skeletal fragility may be an undesirable consequence of chronic FGF21 administration.B one is a dynamic tissue that constantly remodels by balancing osteoblast-mediated bone formation and osteoclast-mediated bone resorption. Under physiological conditions, formation and resorption are tightly coupled, thereby maintaining skeletal homeostasis. Under pathological conditions such as osteoporosis or bone metastasis of cancer, the simultaneously decreased formation and increased resorption lead to the uncoupling of remodeling and bone loss (1-3). Osteoblasts are differentiated from bone marrow mesenchymal stem cells (MSCs), which can also differentiate into adipocytes, depending on both extracellular milieu and intracellular signaling (4-8). In contrast, osteoclasts are differentiated from macrophage precursors in the hematopoietic lineage in response to the cytokine Receptor Activator of NF-κB Ligand (RANKL), depending on the ratio of RANKL to osteoprotegerin (OPG), a RANKL decoy receptor that inhibits osteoclast differentiation (9).Fibroblast growth factor 21 (FGF21) is an atypical member of the FGF family that functions as an endocrine hormone (10, 11). It is a powerful regulator of glucose and lipid metabolism. Physiologically, FGF21 expression is induced both in the liver by prolonged fasting through and in the white adipose tissue by feeding through PPAR-γ activation (15-18). Pharmacologically, administration of recombinant FGF21 protein to diabetic mice and rhesus monkeys strongly enhances insulin sensitivity, decreases plasma glucose and triglyceride, and reduces body weight (19)(20)(21)(22)(23). Hence, FGF21 is a potential drug for the treatment of obesity and diabetes that is currently in clinical trials. However, it is unknown whether FGF21 regulates bone mass. This question is clinically important in light of the already increased skeletal fragility in diabetic patients (24, 25) and the reported bone-loss side effects of the current antidiabetic thiazolidinedione (TZD) drugs such as rosiglitazone, a synthetic PPAR-γ agonist (24,(26)(27)(28)(29)). Here we demonstrate that FGF21 is a potent negative regulator of bone, both physiologically and pharmacologically. ...
The bone resorbing osteoclasts significantly contribute to osteoporosis and cancer bone metastases1-3. MicroRNAs (miRNAs) play important roles in physiology and disease4,5, and present tremendous therapeutic potential6. Nonetheless, how miRNAs regulate skeletal biology is underexplored. Here we identify miR-34a as a novel and critical suppressor of osteoclastogenesis, bone resorption and the bone metastatic niche. miR-34a is down-regulated during osteoclast differentiation. Osteoclastic miR-34a over-expressing transgenic mice exhibit lower bone resorption and higher bone mass. Conversely, miR-34a knockout and heterozygous mice exhibit elevated bone resorption and reduced bone mass. Consequently, ovariectomy-induced osteoporosis, as well as bone metastasis of breast and skin cancers, are diminished in osteoclastic miR-34a transgenic mice, and can be effectively attenuated by miR-34a nanoparticle treatment. Mechanistically, we identify Tgif2 (transforming growth factor-beta-induced factor 2) as an essential direct miR-34a target that is pro-osteoclastogenic. Tgif2 deletion reduces bone resorption and abolishes miR-34a regulation. Together, using mouse genetic, pharmacological and disease models, we reveal miR-34a as a key osteoclast suppressor and a potential therapeutic strategy to confer skeletal protection and ameliorate bone metastasis of cancers.
SUMMARY Nuclear receptors (NRs) are key regulators of gene expression and physiology. Nearly half of all human NRs lack endogenous ligands including estrogen-related receptor α (ERRα). ERRα has important roles in cancer, metabolism and skeletal homeostasis. Affinity chromatography of tissue lipidomes with the ERRα ligand-binding domain (LBD) and subsequent transcriptional assays identified cholesterol as an endogenous ERRα agonist. Perturbation of cholesterol biosynthesis or inhibition of ERRα revealed the interdependence of cholesterol and ERRα. In bone, the effects of cholesterol, statin and bisphosphonate on osteoclastogenesis require ERRα; and consequently, cholesterol-induced bone loss or bisphosphonate osteoprotection are lost in ERRα knockout mice. Furthermore, statin induction of muscle toxicity and cholesterol suppression of macrophage cytokine secretion are impaired by loss or inhibition of ERRα. These findings reveal a key step in ERRα regulation and explain the actions of two highly prescribed drugs, statins and bisphosphonates.
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.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.