The Osteocyte: An Endocrine Cell … and More

R E V I E W The Osteocyte: An Endocrine Cell . . . and More Sarah L. Dallas, Matthew Prideaux, and Lynda F. Bonewald Department of Oral and Craniofacial Sciences, School of Dentistry, University of Missouri-Kansas City, Kansas City, Missouri 64108 I. Introduction II. Osteocyte Differentiation and Embedding III. Morphology of Osteocytes, Their Dendrites, and Lacunocanalicular System IV. Osteocyte Selective Genes/Proteins and Their Potential Functions V. Tools for Studying Osteocytes VI. Osteocyte Mechanosensation and Transduction A. How osteocytes sense loading B. How loading affects osteocyte signaling VII. Osteocytes as Orchestrators of Bone Formation and Resorption VIII. Osteocyte Life, Death, and in Between IX. Osteocytic Perilacunar Remodeling: An Old Concept Rediscovered X. The Osteocyte as an Endocrine Cell XI. Crosstalk Between Osteocytes and Muscle Cells XII. Role of Osteocytes in Disease XIII. Summary and Perspective I. Introduction f the major cell types in bone, osteoblasts and osteoclasts have been defined by their respective functions of bone formation and bone resorption, but osteocytes were defined primarily by their morphology and O ISSN Print 0163-769X ISSN Online 1945-7189 Printed in U.S.A. Copyright © 2013 by The Endocrine Society Received May 2, 2012. Accepted April 16, 2013. First Published Online April 26, 2013 658 edrv.endojournals.org location embedded within mineralized bone matrix rather than by their function. This is because until the past decade or so there has been a lack of clear understanding about the properties of these cells and their important functions in the skeleton. This perception persisted despite the fact that osteocytes make up over 95% of the bone cells in the adult skeleton, with this ratio increasing with age and with the size of the bone. Osteocytes reside in lacunae within the mineralized bone matrix and send their dendritic processes (ranging from 40 –100 per cell [1]) through tiny tunnels called canaliculi to form the osteocyte lacunocanalicular network (Figures 1 and 2), which connects to cells on the bone surface and to the vasculature. A fluid, termed canalicular or bone fluid, that is still not well characterized travels through the lacunocanalicular space and bathes the osteocyte, thereby providing oxygen and nutrients to maintain the viability of the cell in this enclosed environment. Early bone histologists hypothesized various functions for osteocytes, but lacked the tools to test their hypotheses. Today, with the use of transgenic technologies combined Abbreviations: ASARM, acidic serine aspartate-rich MEPE-associated motif; DKK1, Dickkopf1-related protein 1; DMP1, Dentin matrix protein 1; ER-␣, estrogen receptor-␣; FAK, focal adhesion kinase; FGF, fibroblast growth factor; FGFR, FGF receptor; GFP, green fluorescent protein; kb, kilobase; LRP, low-density lipoprotein receptor-related protein; MEPE, matrix extracellular phosphoglycoprotein; NO, nitric oxide; NOS, NO synthase; 1,25(OH)2D, 1,25-dihydroxyvitamin D; OPG, osteoprotegerin; PC1, polycystin 1; PGE2, prostaglandin E2; PHEX, phosphate-regulating gene with homologies to endopeptidases on the X chromosome; PKA, protein kinase A; PKD1, polycystic kidney disease 1; PTH1R, PTH receptor type 1; RANK, receptor activator of nuclear factor ␬-B; RANKL, RANK ligand; SFRP1, secreted frizzled-related protein 1; TRAP, tartrate-resistant acid phosphatase. Endocrine Reviews, October 2013, 34(5):658 – 690 doi: 10.1210/er.2012-1026 Few investigators think of bone as an endocrine gland, even after the discovery that osteocytes produce circulating fibroblast growth factor 23 that targets the kidney and potentially other organs. In fact, until the last few years, osteocytes were perceived by many as passive, metabolically inactive cells. However, exciting recent discoveries have shown that osteocytes encased within mineralized bone matrix are actually multifunctional cells with many key regulatory roles in bone and mineral homeostasis. In addition to serving as endocrine cells and regulators of phosphate homeostasis, these cells control bone remodeling through regulation of both osteoclasts and osteoblasts, are mechanosensory cells that coordinate adaptive responses of the skeleton to mechanical loading, and also serve as a manager of the bone’s reservoir of calcium. Osteocytes must survive for decades within the bone matrix, making them one of the longest lived cells in the body. Viability and survival are therefore extremely important to ensure optimal function of the osteocyte network. As we continue to search for new therapeutics, in addition to the osteoclast and the osteoblast, the osteocyte should be considered in new strategies to prevent and treat bone disease. (Endocrine Reviews 34: 658 – 690, 2013) doi: 10.1210/er.2012-1026 edrv.endojournals.org 659 Figure 1. teoblast and osteoclast function. Osteocytes also act as mechanosensors to control adaptive responses to mechanical loading of the skeleton, and they may be a key target cell for the actions of PTH in bone. The osteocyte therefore appears to integrate hormonal and mechanical signals in the regulation of bone mass. Because osteocytes reside in an enclosed environment for extended periods of time, which can last up to decades, the viability of these cells becomes critical for their function. Not only does the viable osteocyte regulate bone homeostasis, but the dying or apoptotic osteocyte also may play key regulatory roles in sending signals to initiate bone remodeling, particularly when there is a need for bone repair. Autophagy (the process of controlled “self digestion” of the cell contents) also appears to be necessary to sustain the cell within the enclosed environment of the mineralized matrix. Another exciting and unexpected recent discovery is that osteocytes may function in an endocrine manner to regulate phosphate homeostasis through secretion into the circulation of fibroblast growth factor 23 (FGF23). When one thinks of an endocrine organ, tissues such as the pituitary or adrenal glands come to mind, but one would not normally ascribe this function to bone. However, kidney, liver, and heart have all been shown to have endocrine Figure 1. The osteocyte. Schematic representation of an embedded osteocyte functions, and now it appears that bone (and located within its lacuna, illustrating its dendritic processes passing through the bone specifically the osteocyte network) can be matrix (gray shading) within narrow tunnels termed canaliculi. The osteocyte’s dendritic processes interconnect with other osteocytes as well as surface osteoblasts. added to this category. Criteria for designating Note that some osteocyte processes may extend beyond the osteoblast layer to an organ as an endocrine gland are that it must potentially interact with cells in the marrow and that osteocyte dendrites are also in form a system that directly secretes hormones intimate contact with the vasculature. (...truncated)