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Gut Hormones and Their Effect on Bone Metabolism. Potential Drug Therapies in Future Osteoporosis Treatment Gut Hormones and Their Effect on Bone Metabolism. Potential Drug Therapies in Future Osteoporosis Treatment Schiellerup, Sine Paasch; Skov-Jeppesen, Kirsa; Windelov, Johanne Agerlin; Svane, Maria Saur; Holst, Jens Juul; Hartmann, Bolette; Rosenkilde, Mette Marie Published in: Frontiers in Endocrinology DOI: 10.3389/fendo.2019.00075 Publication date: 2019 Document version Publisher's PDF, also known as Version of record Document license: CC BY Citation for published version (APA): Schiellerup, S. P., Skov-Jeppesen, K., Windelov, J. A., Svane, M. S., Holst, J. J., Hartmann, B., & Rosenkilde, M. M. (2019). Gut Hormones and Their Effect on Bone Metabolism. Potential Drug Therapies in Future Osteoporosis Treatment. Frontiers in Endocrinology, 10, [75]. https://doi.org/10.3389/fendo.2019.00075 Download date: 29. Sep. 2021 REVIEW published: 26 February 2019 doi: 10.3389/fendo.2019.00075 Gut Hormones and Their Effect on Bone Metabolism. Potential Drug Therapies in Future Osteoporosis Treatment Sine Paasch Schiellerup 1, Kirsa Skov-Jeppesen 2,3, Johanne Agerlin Windeløv 2,3, Maria Saur Svane 2, Jens Juul Holst 2,3, Bolette Hartmann 2,3 and Mette Marie Rosenkilde 1* 1 Laboratory of Molecular Pharmacology, Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark, 2 Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark, 3 Faculty of Health and Medical Sciences, Novo Nordisk Foundation (NNF) Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark Bone homeostasis displays a circadian rhythm with increased resorption during the Edited by: night time as compared to day time, a difference that seems—at least partly—to be Marco Falasca, caused by food intake during the day. Thus, ingestion of a meal results in a decrease Curtin University, Australia in bone resorption, but people suffering from short bowel syndrome lack this response. Reviewed by: Giulia Cantini, Gut hormones, released in response to a meal, contribute to this link between the gut Università degli Studi di Firenze, Italy and bone metabolism. The responsible hormones appear to include glucose-dependent Ayse Zengin, Monash University, Australia insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), known as incretin *Correspondence: hormones due to their role in regulating glucose homeostasis by enhancing insulin Mette Marie Rosenkilde release in response to food intake. They interact with their cognate receptors (GIPR [email protected] and GLP-1R), which are both members of the class B G protein-coupled receptors Specialty section: (GPCRs), and already recognized as targets for treatment of metabolic diseases, such as This article was submitted to type 2 diabetes mellitus (T2DM) and obesity. Glucagon-like peptide-2 (GLP-2), secreted Cellular Endocrinology, concomitantly with GLP-1, acting via another class B receptor (GLP-2R), is also part a section of the journal Frontiers in Endocrinology of this gut-bone axis. Several studies, including human studies, have indicated that Received: 20 September 2018 these three hormones inhibit bone resorption and, moreover, that GIP increases bone Accepted: 28 January 2019 formation. Another hormone, peptide YY (PYY), is also secreted from the enteroendocrine Published: 26 February 2019 L-cells (together with GLP-1 and GLP-2), and acts mainly via interaction with the class Citation: Schiellerup SP, Skov-Jeppesen K, A GPCR NPY-R2. PYY is best known for its effect on appetite regulation, but recent Windeløv JA, Svane MS, Holst JJ, studies have also shown an effect of PYY on bone metabolism. The aim of this review Hartmann B and Rosenkilde MM is to summarize the current knowledge of the actions of GIP, GLP-1, GLP-2, and PYY (2019) Gut Hormones and Their Effect on Bone Metabolism. Potential Drug on bone metabolism, and to discuss future therapies targeting these receptors for the Therapies in Future Osteoporosis treatment of osteoporosis. Treatment. Front. Endocrinol. 10:75. doi: 10.3389/fendo.2019.00075 Keywords: gut hormones, bone metabolism, GIP, GLP-1, GLP-2, PYY, osteoporosis Frontiers in Endocrinology | www.frontiersin.org 1 February 2019 | Volume 10 | Article 75 Schiellerup et al. Gut Hormones and Bone Metabolism INTRODUCTION—BONES population, in turn, regulates the activity of the osteoclast population and vice versa (Figure 1). Osteocytes regulate the Bone is a tissue with very important mechanical functions, osteoblasts via signaling molecules including fibroblast growth providing rigidity, strength and shape, and is essential for factor-23 (FGF-23), bone morphogenetic proteins (BMPs), and movement. However, in spite of its apparently static structure, sclerostin, whereas some of the key signaling molecules involved bone tissue is dynamic and undergoes a constant remodeling, in the osteoblastic regulation of the osteoclasts include RANKL, consisting of processes of bone resorption and bone formation. that induces osteoclast activity, and osteoprotegerin (OPG), that Proper balance is controlled by the coupling of these two counters the effect of RANKL. Malfunctions in some of these processes, and involves a number of coordinated signaling regulatory mechanisms are known to cause bone disorders; mechanisms. In normal bone remodeling, a balance between mutations of FGF-23, for example, are known to cause autosomal bone resorption (mediated by osteoclasts) and bone formation dominant hypophosphatemic rickets (ADHR). Some of these (mediated by osteoblasts) is maintained to ensure a constant regulatory factors, including RANKL and sclerostin, are targets bone mass. An imbalance between bone resorption and bone for therapies that aim to alter the balance between the osteoblast formation may occur under certain pathological conditions, and activity and osteoclast activity in order to treat osteoporosis, lead to abnormal bone remodeling and the development of which is characterized by an imbalance between these activities. bone disorders (1). Bone also has an important function as a When bone is resorbed, a carboxy-terminal telopeptide of type reservoir for calcium and phosphate, bound in the matrix as I collagen (CTX) is liberated and released into the blood stream. hydroxyapatite, and bone tissue is, therefore, along with the Levels of circulating CTX are, therefore, used as a biomarker intestine and kidneys, important for the maintenance of proper for bone resorption. CTX levels show diurnal variation, peaking calcium levels (2–4). during the night-time, and showing a nadir in the late afternoon. Histologically, there are two main types of bone, cortical and As fasting is associated with a flattened circadian rhythm (6), with trabecular. These have different structure and properties. Cortical the day-time decline in CTX levels being eliminated, ingestion bone has a highly organized, lamellar structure, providing planar of food seems to be the explanation for the daytime suppression strength. Generally, bones have an outer layer of cortical bone (7, 8). Bone formation can be assessed by measurements of with trabecular bone beneath. The weight-bearing long bones, an amino-terminal propeptide of type 1 procollagen (P1NP) such as the femur and humerus, mainly have cortical bone in or by measuring the protein osteocalcin, which is secreted their shafts. Trabecular bone has a more irregular and less dense from osteoblasts. structure, consisting of interconnecting bars, or trabeculae, with bone marrow filling the gaps. The number of trabeculae has been shown to be more important than their thickness in regard to the THE GUT-BONE AXIS strength of the bone (5). Bone tissue consists of cellular elements within an The gut and the bones are connected through the gut-bone axis, extracellular matrix. The cellular components are the osteoblasts, and this interaction is mediated by hormones secreted from the the osteocytes and the osteoclasts. The bone-forming osteoblasts intestine. These hormones are secreted in response to food intake derive from mesenchymal stem cells that differentiate into and causes a decrease in bone resorption (7–9), and are thus osteoprogenitor cells, a process that is dependent on the mediators of the adaptation of bones to nutrient availability. Bone Wnt/β-catenin pathway. With age, the osteoblasts become resorption is increased during the night as compared to the day, buried in the matrix and are now designated osteocytes. and this day-time suppression is eliminated by fasting, further These cells communicate with each other and with other cells, affirming the role of the gastrointestinal hormones in the control particularly those on the surface of the bone tissue, through of bone homeostasis. Many hormones are secreted from the gut dendritic processes in canaliculi in the bone, allowing them [for a recent review see Gribble and Reimann (10)], but the to regulate bone-turnover in response to mechanical stress focus of this review will be on the incretin hormones glucose- (1). Osteoclasts are multinucleated cells, derived from the dependent insulinotropic polypeptide (GIP) and glucagon-like macrophage/monocyte lineage, which resorb bone on the growth peptide-1 (GLP-1), as well as glucagon-like peptide-2 (GLP-2) surface. The differentiation into mature osteoclasts is dependent and peptide YY (PYY). on activation by the receptor activator of nuclear factor κB GIP (secreted from enteroendocrine K-cells) and GLP-1 (NF-κB) ligand (RANKL) and monocyte colony
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