Osteocytes: master orchestrators of bone

Abstract

Osteocytes comprise the overwhelming majority of cells in bone and are its only true "permanent" resident cell population. In recent years, conceptual and technological advances on many fronts have helped to clarify the role osteocytes play in skeletal metabolism and the mechanisms they use to perform them. The osteocyte is now recognized as a major orchestrator of skeletal activity, capable of sensing and integrating mechanical and chemical signals from their environment to regulate both bone formation and resorption. Recent studies have established that the mechanisms osteocytes use to sense stimuli and regulate effector cells (e.g., osteoblasts and osteoclasts) are directly coupled to the environment they inhabit-entombed within the mineralized matrix of bone and connected to each other in multicellular networks. Communication within these networks is both direct (via cell-cell contacts at gap junctions) and indirect (via paracrine signaling by secreted signals). Moreover, the movement of paracrine signals is dependent on the movement of both solutes and fluid through the space immediately surrounding the osteocytes (i.e., the lacunar-canalicular system). Finally, recent studies have also shown that the regulatory capabilities of osteocytes extend beyond bone to include a role in the endocrine control of systemic phosphate metabolism. This review will discuss how a highly productive combination of experimental and theoretical approaches has managed to unearth these unique features of osteocytes and bring to light novel insights into the regulatory mechanisms operating in bone.

Figure 1

Schematic representation of key microstructural/ultrastructural features of osteocytes implicated in mechanosensing. A) Transmission electron (TEM) photomicrograph of an osteocyte process containing bundled F-actin (large black structures indicated by white arrow). Actin bundles in osteocyte processes increase their stiffness and limits membrane deformation.* B) TEM photomicrograph of proteoglycan tethering elements (black arrows) bridging osteocyte cell process to bony canalicular wall. Tethering proteoglycans such as perlecans are spaced approximately every 40 nm along the osteocyte process. These proteoglycan tethers exert a resistance to mechanical loading induced fluid flow, and the resulting drag force may be sensed at the cell process membrane. C) Fluorescent immunohistochemical (IHC) staining showing that β1 integrins (white arrows) are located only on osteocyte cell bodies.** D) TEM photomicrographs demonstrating the discrete protrusions from the canalicular wall (matrix hillock protrusions), which contact osteocyte processes; comparable direct bone-to membrane-attachment sites are not seen in osteocyte lacunae. E) Fluorescent IHC staining for β3 integrins (white arrows) are present in a punctate pattern along osteocyte processes. β3 integrins have shown to have a similar periodicity and spacing pattern to matrix hillock protrusions, and are absent from cell bodies. The localized strains at these adhesion sites caused by fluid flow-induced membrane deformations would be one to two orders of magnitude larger than whole-tissue strains (i.e. “local strain amplification”). *** [* Figure from You et al. [13] reprinted with permission; ** and ***: Figures from McNamara et al. [10], reprinted with permission.]

Figure 2

Schematic summary of osteocytes in bone and their signaling to regulate bone formation. A) Osteocytes underlying resting surface of bone lining cells. These osteocytes constitutively produce inhibitors of bone formation (i.e. sclerostin and DKK-1; shown in red). When osteocyte production of the bone formation inhibitors ceases, bone formation is activated. In such circumstances, (B), osteocytes underlying regions of active bone formation can produce signals that promote osteoblast activity (i.e. PGE₂, NO, and IGF-1; shown in green)

Figure 3

Schematic summary of the role of osteocytes in triggering bone resorption. A) Microcracks in bone caused by fatigue loading lead to highly localized osteocyte apoptosis (shown in white) surrounding the microcrack. B) Recent studies show that surviving osteocytes immediately neighboring the region of apoptosis upregulate production of pro-osteoclastogenic signals (i.e. RANKL, and others). This increase in RANKL signaling is caused by the osteocyte apoptosis, not the bone microdamage itself. Healthy osteocytes farther from the microdamage site do not produce osteoclastogenic signals. Osteoclasts are then recruited to resorb damaged and apoptotic osteocytes during the microdamage repairing process.