Functions of the osteocyte network in the regulation of bone mass

Abstract

Osteocytes establish an extensive intracellular and extracellular communication system via gap-junction-coupled cell processes and canaliculi throughout bone and the communication system is extended to osteoblasts on the bone surface. The osteocyte network is an ideal mechanosensory system and suitable for mechanotransduction. However, the overall function of the osteocyte network remains to be clarified, since bone resorption is enhanced by osteocyte apoptosis, which is followed by a process of secondary necrosis attributable to the lack of scavengers. The enhanced bone resorption is caused by the release of intracellular content, including immunostimulatory molecules that activate osteoclastogenesis through the canaliculi. Therefore, a mouse model is required in which the osteocyte network is disrupted but in which no bone resorption is induced, in order to evaluate the overall functions of the osteocyte network. One such model is the BCL2 transgenic mouse, in which the osteocyte network, including both intracellular and extracellular networks, is disrupted. Another model is the osteocyte-specific Gja1 knockout mouse, in which intercellular communication through gap junctions is impaired but the canalicular system is intact. Combining the findings from these mouse models with previous histological observations showing the inverse linkage between osteocyte density and bone formation, we conclude that the osteocyte network enhances bone resorption and inhibits bone formation under physiological conditions. Further, studies with BCL2 transgenic mice show that these osteocyte functions are augmented in the unloaded condition. In this condition, Rankl upregulation in osteoblasts and Sost upregulation in osteocytes are, at least in part, responsible for enhanced bone resorption and suppressed bone formation, respectively.

Fig. 1

Osteocyte death and bone resorption. Cells die mainly through one of three pathways: apoptosis, autophagic cell death and necrosis. As osteocytes at the terminal phase of apoptosis or autophagic cell death are not engulfed by phagocytes, the process of secondary necrosis ensues. After cell rupture, immunostimulatory molecules including high-mobility group box 1 (HMGB1), S100, heat shock protein (HSP), adenosine triphosphate (ATP) and uric acid are released from lacunae through canaliculi to the bone surface and vascular channels, where they facilitate the recruitment and activation of macrophages, thereby promoting the production of proinflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin 6 (IL-6) and interleukin 1 (IL-1), which induce osteoclastogenesis and bone resorption. Apoptotic osteocytes release osteoclastogenesis-promoting factors, including soluble receptor activator of nuclear factor κ-B ligand (sRankl), IL-6 and soluble IL-6 receptor (sIL-6R) and induce TNF-α expression in osteoclast precursors in vitro

Fig. 2

Regulation of bone mass by the osteocyte network. a Regulation of bone mass under physiological conditions. The osteocyte network mildly stimulates osteoclastogenesis and bone resorption and mildly inhibits osteoblast function and bone formation. Rankl expression in osteoblasts and sclerostin (Sost) expression in osteocytes are, at least in part, responsible for the enhanced bone resorption and suppressed bone formation, respectively. Both Rankl and osteoprotegerin (Opg) are highly expressed in osteocytes and Opg seems to be trapped by Rankl on the surface of osteocytes. sRankl secreted by osteocytes might be involved in the regulation of osteoclastogenesis (dashed arrow). b Regulation of bone mass in the unloaded condition. The osteocyte network strongly stimulates osteoclastogenesis and bone resorption and strongly inhibits osteoblast function and bone formation. The osteocyte network enhances Rankl expression in osteoblasts and Sost expression in osteocytes in the unloaded condition. The signals from osteocytes that stimulate Rankl expression in osteoblasts remain to be identified. Upregulation of Rankl in osteocytes in the unloaded condition is controversial. In a, b, the thickness of the lines and arrows reflects the strength of the effects and the height of the osteoblasts reflect their activities