Recent progress in osteocyte research.

Review Article Endocrinol Metab 2013;28:255-261 http://dx.doi.org/10.3803/EnM.2013.28.4.255 pISSN 2093-596X · eISSN 2093-5978 Recent Progress in Osteocyte Research Paola Divieti Pajevic Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA The last decade has seen an exponential increase in our understanding of osteocytes function and biology. These cells, once considered inert by-standers trapped into the mineralized bone, has now risen to be key regulators of skeletal metabolism, mineral homeostasis, and hematopoiesis. As tools and techniques to study osteocytes improved and expanded, it has become evident that there is more to these cells than initially thought. Osteocytes are now recognized not only as the key responders to mechanical forces but also as orchestrators of bone remodeling and mineral homeostasis. These cells are the primary source of several important proteins, such as sclerostin and fibroblast growth factor 23, that are currently target as novel therapies for bone loss (as the case for antisclerostin antibodies) or phosphate disorders. Better understanding of the intricate cellular and molecular mechanisms that govern osteocyte biology will open new avenue of research and ultimately indentify novel therapeutics to treat bone and mineral disorders. This review summarizes novel findings and discusses future avenues of research. Keywords: Osteocytes; Sclerostin; Mineral homeostasis; Bone homeostasis INTRODUCTION Our understanding of the function of osteocytes has expanded dramatically over the last decade primarily due to the identification of osteocytes specific markers, such as dentin matrix protein 1 (DMP1) and SOST/sclerostin, that has allowed, for the first time a closer look at the biology of these cells. Osteocytes, the cells deeply entrapped into the mineralized matrix, have emerged as key regulators not only of skeletal and mineral homeostasis, but also hematopoiesis. This review will summarize novel findings in osteocyte biology and future avenues of research. THE OSTEOCYTES Osteocytes are postmitotic, terminally differentiated osteoCorresponding author: Paola Divieti Pajevic Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, 50 Blossom Street, Boston, MA 02114, USA Tel: +1-617-726-6184, Fax: +1-617-726-7543, E-mail: . harvard.edu blasts that during the process of matrix mineralization remain entrapped in the mineralizing matrix that they are actively synthesizing. They reside both in the mineralized matrix and in the newly formed osteoid. Earlier work of Gaillard et al. [1] and Rutishauser and Majno [2], described two stages into the life of an osteocyte; an early stage (young osteocyte) in which the cell is smaller in size, reside into the osteoid and do not express alkaline phosphatase and a late stage (mature osteocyte) in which the larger cell re-express alkaline phosphatase and is deeply embedded in the mineralized bone. The larger cell will then degenerate and leave an empty lacuna [1]. This classification has been recently revised to include an additional stage of differentiation: according to their spatial localization and gene expression, these cells are now divided into osteoid, mineralizing, and the mature osteocytes [3]. The osteoid, or nascent osteocyte is characterized by a relative proximCopyright © 2013 Korean Endocrine Society This is an Open Access article distributed under the terms of the Creative Com mons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribu tion, and reproduction in any medium, provided the original work is properly cited. www.e-enm.org 255 Pajevic PD ity to the endosteal (and possibly periostal) surface and the expression of transcripts such as E11/gp38/podoplain [4], matrix extracellular phosphoglycoprotein (MEPE) and phosphateregulating gene with homologies to endopeptidases on the X chromosome (Phex). This cell, opposite to the more mature osteocyte, is negative for sclerostin and fibroblast growth factor (FGF)-23 expression but does express DMP1, as elegantly demonstrated by Kalajzic et al. [5] in a recent review. It is not clear, however, if osteoid, mineralizing and mature osteocytes exert different biological functions or if they all work as mechanosensor and skeletal regulators. Indeed recent studies suggest that cortical and trabecular osteocytes might have distinct roles with the former being the sensor of load while the latter being the controller of bone metabolism. Windahl et al. [6], for example, reported that estrogen receptor-α ablation in osteocytes differentially affects trabecular and cortical bone compartments in males mice. Marotti et al. [7] and Palumbo et al. [8,9] have extensively described the morphological changes that accompany the transformation from a motile osteoblast into an entombed osteocyte. They demonstrate, by histological analysis of newborn rabbit bones, that the formation of osteocyte cytoplasmic processes is asynchronous and asymmetrical and precede the mineralization of the organic matrix. Moreover, osteocytes are evolutionary highly conserved and the organized structure of these cells within a mineralized matrix is present in bone specimens from Tyrannosaurus rex, dating back more than 80 million of years ago, clearly indicating an important role for these cells in skeletal metabolism [10]. Osteocytes communicate with each other and with cells at the endosteal and periosteal surface through an extensive and intricate system of canaliculi. These cells are also in close proximity of capillary and vessels, raising the hypothesis that osteocytes might function as an endocrine organ and directly secrete proteins, such as FGF-23, Phex, or sclerostin into the circulation [11]. Moreover, the osteocytic network, with its extensive system, is an ideal structure to sense mechanical loading and control mineral homeostasis. It has been postulated that osteocytes can send signals for both bone resorption and formation and thus orchestrate a proper cycle of remodeling, as discussed in details below. OSTEOCYTE FUNCTIONS: MECHANOTRANSDUCTION What are the functions of an osteocyte? It has been recognized 256 www.e-enm.org for over 30 years that osteocytes are mechanosensor of bone. They are indeed the cells capable of sensing mechanical forces applied to the skeleton and transform these forces into biological stimuli. It is now widely accepted that the cell perceives forces in the form of shear stress created by the flow of fluid inside the lacuna-canalicular network. It has been proposed that the flow derives from both the compression induced by loading and the extravascular pressure. Efforts to physically measure and quantify this flow are currently ongoing and recent reports suggest that osteocytes are subjected to forces in the order of 5 Pa [12]. Although the theory that osteocytes are the mechanosensor of bone has (...truncated)