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Beyond Mineralisation: Metabolic Functions for Matrix Mineralisation Regulators

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Beyond Mineralisation: Metabolic Functions for Matrix Mineralisation Regulators 245 2 Journal of F Roberts et al. Mineralisation regulators and 245:2 R11–R22 Endocrinology metabolism REVIEW Beyond mineralisation: metabolic functions for matrix mineralisation regulators Fiona Roberts, Greg Markby, Scott Dillon, Colin Farquharson and Vicky E MacRae Functional Genetics and Development, The Roslin Institute, The University of Edinburgh, Edinburgh, UK Correspondence should be addressed to F Roberts: [email protected] C Farquharson is co-Editor-in-Chief of Journal of Endocrinology. He was not involved in the review or editorial process for this paper, on which he is listed as an author Abstract The physiological mineralisation of skeletal tissues, as well as the pathological Key Words mineralisation of soft tissues involves a fine balance between regulators that either f endocrine promote or inhibit the process. In recent years, several studies have advocated a non- f metabolism skeletal role for some of these mineralisation regulators in a range of human diseases, f mineralisation including diabetes, cardiovascular disease, obesity and neurodegenerative disease. This f bone is an emerging area of interest and the functional roles and mechanisms of action of these various endocrine factors, phosphatases and phosphodiesterase’s in important pathologies are the focus of this review. Mechanistic insight of the pathways through which these acknowledged regulators of skeletal mineralisation act beyond the skeleton has the potential to identify druggable targets for commonly experienced morbidities, Journal of Endocrinology notably those related to metabolism and metabolic syndrome. (2020) 245, R11–R22 Introduction Bone has numerous classical functions including organ its structure across length scales, conveying remarkable protection, calcium and phosphate ion homeostasis, and mechanical properties in a range of contexts from the facilitation of movement. The skeleton is structurally ear ossicles to the load-bearing bones of the lower limb suited to function: strong and flexible enough to bear load (Fyhrie 2010, Hart et al. 2017, Schwarcz et al. 2017). without damage, yet light enough to allow locomotion. The maintenance of bone quality is critical to Bone is composed of organic constituents including facilitate its function (Clarke 2008). To ensure this, there collagenous proteins (principally type I collagen) and is life-long remodelling of the bone matrix (Kenkre & non-collagenous proteins (including but not limited to Bassett 2018) which involves the coordinated function osteocalcin, osteonectin, osteopontin (OPN) and bone of two orthologous cell types – the osteoblast (which sialoprotein (BSP)) (Termine 1988, Roach 1994, Shekaran forms bone) and the osteoclast (which resorbs bone). & García 2011, Dillon et al. 2019). Bone also contains non- During bone formation, polarised osteoblasts secrete organic poorly crystalline substituted hydroxyapatite (HA) an extracellular matrix (ECM) which contains a variety mineral and water (Glimcher & Muir 1984, Clarke 2008, of collagenous and non-collagenous proteins, which Stock 2015). Within bone, a large population of living cells subsequently mineralises over a period of time. The (the osteocytes) are entombed in the mineralised matrix. controlled mineralisation of this osteoid is critical in Bone’s material properties are a function of both the allowing the anatomically specialised functions of relative proportions of these elementary constituents and bone. The emergence of sophisticated technologies https://joe.bioscientifica.com © 2020 Society for Endocrinology https://doi.org/10.1530/JOE-19-0460 Published by Bioscientifica Ltd. Printed in Great Britain Downloaded from Bioscientifica.com at 09/27/2021 05:03:47PM via free access -19-0460 Journal of F Roberts et al. Mineralisation regulators and 245:2 R12 Endocrinology metabolism in cell biology, imaging of genetically altered mouse critical role they play in ensuring that bone mineralises models and mineral phase chemical characterisation physiologically. The mineralisation of bone is dependent has improved our understanding of the fine control of upon optimum concentrations of calcium (Ca2+) and ECM mineralisation during skeletal development and the inorganic phosphate (Pi), and the precise mechanism(s) resultant pathological ramifications. by which mineral is embedded within the collagen fibrils Both bone formation and bone resorption are of the ECM is tightly regulated. The regulatory substances energetically costly. This has led to a hypothesis, whereby include magnesium ions, carbonate, proteoglycans, energy metabolism and bone formation regulate one polyphosphates and poly-phosphorylated molecules and another in a feedback loop. Following recent work which the small integrin-binding ligand, N-linked glycoprotein, led to the discovery of metabolically active osteocalcin, non-collagenous proteins (including OPN, BSP, dentin a hormone secreted specifically by the osteoblast to matrix protein, dentin sialophosphoprotein and matrix promote insulin sensitivity, further evidence has emerged extracellular phosphogylocprotein) (George et al. 1993, for a metabolic role for bone (Fig. 1) (Lee et al. 2007 Ferron Sodek et al. 1995, Macdougall et al. 1998, Ganss et al. et al. 2010, Clemens & Karsenty 2011, Wei & Karsenty 1999, Qin et al. 2002, 2004, Nampei et al. 2004, Margolis 2015). Contemporary research has revealed varied roles et al. 2014). The mechanisms responsible for the initiation for key regulators of ECM mineralisation in a range of of matrix mineralisation are not fully understood. It has physiological and pathophysiological processes. This been proposed that the pre-formed extracellular collagen review will explore these emerging roles. I template mediates mineral nucleation (Christoffersen & Landis 1991, Landis & Silver 2009, Nudelman et al. 2013). Others have proposed that matrix vesicles (MVs) 2+ Classic functions of mineralisation regulators control localised accumulation of Ca and Pi (Anderson, 1969, 1995, Ali et al. 1970). MVs are small (100–300 Before elaborating on the function of mineralisation nm diameter) extracellular membrane-bound particles regulators beyond the skeleton, we will address the released by osteoblasts and chondrocytes. MVs are Figure 1 2+ Schematic representation of matrix mineralisation regulators. The hydroxyapatite (HA) crystals consist of Pi and Ca . In matrix vesicles (MVs), which are secreted by osteoblasts, Pi accumulates via the actions of PiT1/2 phosphate transporters which shuttle in extracellular Pi (ePi) from TNAP hydrolysis of PPi. Pi is also generated in MVs by (PHOSPHO1) which hydrolyses phosphomonoesters phosphoethanolamine (PEA) and phosphocholine (PChol). Annexin 2+ is responsible for transporting Ca into the MV. ENPP1 generates extracellular PPi (ePPi) and this PPi is further hydrolysed by TNAP to yield Pi. ANK transports intracellular PPi (iPPi) to the ECM. The iPPi drives the expression of osteopontin, which inhibits HA formation. RANKL promotes osteoclastogenesis and causes the formation of acidic osteoclast resorption lacunae. The acidic pH drives the formation of metabolically active OCN via de-carboxylation. Metabolically active OCN acts systemically on the adipose tissue skeletal muscle and liver. https://joe.bioscientifica.com © 2020 Society for Endocrinology https://doi.org/10.1530/JOE-19-0460 Published by Bioscientifica Ltd. Printed in Great Britain Downloaded from Bioscientifica.com at 09/27/2021 05:03:47PM via free access Review Journal of F Roberts et al. Mineralisation regulators and 245:2 R13 Endocrinology metabolism considered to provide a locally protected environment Mumm et al. 2001, van den Bos et al. 2005, Linglart & 2+ within which Ca and Pi accumulate in an amorphous Biosse-Duplan, 2016). Global Akp2 knockout mice present state, a process that is regulated by a complex network of with elevated urinary PPi levels and recapitulate the bone pathways (Wuthier & Lipscomb 2011). mineralisation abnormalities noted in patients with Systemic hormonal regulators of ECM mineralisation hypophosphatasia (Narisawa et al. 1997, Fedde et al. 1999) include 1,25-dihydroxyvitamin D3, fibroblast growth TNAP also regulates ectopic calcification Narisawa( et al. factor 23 (FGF-23) and parathyroid hormone (PTH). These 1997, Fedde et al. 1999, Anderson et al. 2004). Increased 2+ regulators control Ca and Pi balance via actions on the TNAP activity in the vasculature is associated with medial 2+ intestine and kidney to ensure Ca and Pi availability for vascular calcification, vascular stiffness and resultant HA formation in bone (Parfitt 1976, Canalis & Delany heart failure (Sheen et al. 2015). 2002, Rowe 2012). Furthermore, the mineralisation process Orphan phosphatase 1 (PHOSPHO1; EC 3.1.3.75) is also mediated by several mineralisation inhibitors. Of is also responsible for generating Pi to facilitate skeletal notable importance is inorganic pyrophosphate (PPi) mineralisation through its highly specific phosphatase which has long been acknowledged as an inhibitor of activity (Roberts et al. 2007, Dillon et al. 2019). Present skeletal mineralisation and regulator of physiological within the lumen of the MV, PHOSHPO1 exhibits mineralisation (Fleisch et al. 1966). Critically, PPi inhibits high specificity for phosphocholine (PCho) and the growth, dissolution and formation of HA crystals phosphoethanolamine (PEA), which it cleaves to generate (Fleisch & Bisaz 1962a,b, Fleisch et al. 1966). Therefore, intra-vesicular Pi (Houston et al. 1999, Stewart et al. 2006,
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