The Osteocyte: New Insights

Abstract

Osteocytes are an ancient cell, appearing in fossilized skeletal remains of early fish and dinosaurs. Despite its relative high abundance, even in the context of nonskeletal cells, the osteocyte is perhaps among the least studied cells in all of vertebrate biology. Osteocytes are cells embedded in bone, able to modify their surrounding extracellular matrix via specialized molecular remodeling mechanisms that are independent of the bone forming osteoblasts and bone-resorbing osteoclasts. Osteocytes communicate with osteoclasts and osteoblasts via distinct signaling molecules that include the RankL/OPG axis and the Sost/Dkk1/Wnt axis, among others. Osteocytes also extend their influence beyond the local bone environment by functioning as an endocrine cell that controls phosphate reabsorption in the kidney, insulin secretion in the pancreas, and skeletal muscle function. These cells are also finely tuned sensors of mechanical stimulation to coordinate with effector cells to adjust bone mass, size, and shape to conform to mechanical demands.

Keywords: FGF23; RANKL; mechanosensation; osteocytes; perilacunar remodeling; sclerostin.

Figure 1

(a) The graph shows the relative temporal expression of keratocan (KTN), a marker for osteoblasts; E11/gp38 (E11), a marker of early embedding osteocytes; dentin matrix protein 1 (DMP1), an early osteocyte marker responsible for mineralization; neuropeptide Y (NPY), a neurotransmitter expressed in maturing osteocytes; and MEPE and SOST, both markers for late, mature osteocytes. (b) The Goldner-stained bone section below shows marrow, the surface osteoblasts (①), the embedding osteoid osteocyte (②), early mineralizing osteocytes (③), and mature osteocytes (④). The time scale for the expression graph in panel a corresponds temporally to the differentiation process represented histologically in panel b.

Figure 2

(a) Three-dimensional reconstruction image of the avian osteocyte network by IMARIS software. Note the ordered array of the osteocytes in chick bone. (b) Field emission scanning electron microscope images of chick osteocyte. Adapted with permission from Reference . Copyright 1998, John Wiley & Sons.

Figure 3

Backscatter scanning electron microscopy of a resin-filled, acid-etched cross section of murine long bone. Note the extensive connections between lacunae. (Inset) Note the dendrite-filled canalicular connections with the bone surface.

Figure 4

OmGFP66 cells form bone-like structures with a lacunar and osteocyte morphology resembling in vivo bone. Maximal Z-projected confocal images of (a) an OmGFP66 bone-like structure from a day-28 culture and (b) a 7-day-old Dmp1-mGFP transgenic mouse calvarium. Green denotes Dmp1-mGFP and red the alizarin reed staining for mineral. Note the similarities in morphology and spacing of the Dmp1-mGFP-positive osteocytes and similar appearance of the mineralized lacunae by alizarin red fluorescence. Adapted with permission from Reference . Copyright 2019, John Wiley & Sons.

Figure 5

(Top) Osteocytes function as mechanosensory cells that mediate loading effects in bone through enhanced release or inhibition of regulatory molecules. (Bottom) Bone homeostasis cells regulate the normal process of bone remodeling via activation of osteoclasts (left) and osteoblasts (right) by distinct pathways. (Inset) Endocrine cells regulate such diverse and distant processes as phosphate handling in the kidney and muscle maintenance in the limbs and trunk. Abbreviations: ATP, adenosine triphosphate; DKK1, Dickkopf gene codes for the protein that is an inhibitor of WNT signaling; FGF23, fibroblast growth factor 23; IGF-1, insulin-like growth factor 1; M-CSF, macrophage colony stimulating factor; NO, nitric oxide; OPG, osteoprotegerin; PGE₂, prostaglandin E₂; RANKL, receptor activator of NF-κB ligand; SOST, gene coding for the protein sclerostin, a specific inhibitor of WNT signaling.