Gut Hormones and Their Effect on Bone Metabolism. Potential Drug Therapies in Future Osteoporosis Treatment

Abstract

Bone homeostasis displays a circadian rhythm with increased resorption during the night time as compared to day time, a difference that seems-at least partly-to be caused by food intake during the day. Thus, ingestion of a meal results in a decrease in bone resorption, but people suffering from short bowel syndrome lack this response. Gut hormones, released in response to a meal, contribute to this link between the gut and bone metabolism. The responsible hormones appear to include glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), known as incretin hormones due to their role in regulating glucose homeostasis by enhancing insulin release in response to food intake. They interact with their cognate receptors (GIPR and GLP-1R), which are both members of the class B G protein-coupled receptors (GPCRs), and already recognized as targets for treatment of metabolic diseases, such as type 2 diabetes mellitus (T2DM) and obesity. Glucagon-like peptide-2 (GLP-2), secreted concomitantly with GLP-1, acting via another class B receptor (GLP-2R), is also part of this gut-bone axis. Several studies, including human studies, have indicated that these three hormones inhibit bone resorption and, moreover, that GIP increases bone formation. Another hormone, peptide YY (PYY), is also secreted from the enteroendocrine L-cells (together with GLP-1 and GLP-2), and acts mainly via interaction with the class A GPCR NPY-R2. PYY is best known for its effect on appetite regulation, but recent studies have also shown an effect of PYY on bone metabolism. The aim of this review is to summarize the current knowledge of the actions of GIP, GLP-1, GLP-2, and PYY on bone metabolism, and to discuss future therapies targeting these receptors for the treatment of osteoporosis.

Keywords: GIP; GLP-1; GLP-2; PYY; bone metabolism; gut hormones; osteoporosis.

Figure 1

Bone remodeling is a process that takes place in the bone remodeling unit (BMU). BMU consists of bone resorbing osteoclasts (OC), bone forming osteoblasts (OB), and osteocytes. The process is regulated by local signals between the cells and by external stimuli. OBs stimulate OC precursors to differentiate into mature OCs by secreting monocyte colony stimulating factor (M-CSF) and RANKL, but may also inhibit the same cells by secreting osteoprotegerin (OPG) that scavenges RANKL, preventing it from binding to the RANK receptors on the OC precursors. OBs are derived from mesenchymal stem cells, a process that is dependent on the Wnt/β-catenin pathway. This pathway is inhibited by sclerostin, which is secreted from osteocytes. Several other factors which affect bone remodeling are mentioned in the text (FGF-23, BMP), but are not shown in this figure.

Figure 2

The gut hormones GLP-2, GIP, GLP-1, and PYY, have been shown to affect bone metabolism. The osteoblast increases its activity in response to GIP and GLP-2 (anabolic effects), and decreases its activity in response to PYY (catabolic effects). The exact mechanism of GLP-2 remains to be elucidated. GLP-2 has been shown to be anti-resorptive in vivo, an effect which may be direct or indirect. GIP decreases osteoblast activity, and GLP-1 also seems to decrease resorption. PYY's effect, if there is one, has yet to be determined. GLP-2 has been shown to decrease bone resorption, but it is uncertain whether it affects the osteoclast directly. GIP has been shown to affect the osteoclast, reducing bone resorption. This has also been shown for GLP-1, while it has also been shown that it increases differentiation. There is no certain effect of PYY on osteoclasts (Bone figure from Somersault18:24, CCBY-NC-SA 4.0).