Mouse Models for the Evaluation of Osteocyte Functions
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Osteocytes establish an extensive intracellular and extracellular communication systemvia gap junction-coupled cell processes and canaliculi, through which cell processes passthroughout bone, and the communication system is extended to osteoblasts on thebone surface. To examine the osteocyte function, several mouse models were estab-lished. To ablate osteocytes, osteocytes death was induced by diphtheria toxin. However,any types of osteocyte death result in necrosis, because dying osteocytes are not phago-cytosed by scavengers. After the rupture of cytoplasmic membrane, immunostimulatorymolecules are released from lacunae to bone surface through canaliculi, and stimulatemacrophages. The stimulated macrophages produce interleukin (IL)-1, IL-6, and tumornecrosis factor-alpha (TNF- α), which are the most important proinflammatory cytokinestriggering inflammatory bone loss. Therefore, the osteocyte ablation results in necrosis-induced severe osteoporosis. In conditional knockout mice of gap junction protein al-pha-1 (GJA1), which encodes connexin 43 in Gap junction, using dentin matrix protein 1(DMP1) Cre transgenic mice, osteocyte apoptosis and enhanced bone resorption occur,because extracellular communication is intact. Overexpression of Bcl-2 in osteoblasts us-ing 2.3 kb collagen type I alpha1 (COL1A1) promoter causes osteocyte apoptosis due tothe severe reduction in the number of osteocyte processes, resulting in the disruption ofboth intracellular and extracellular communication systems. This mouse model unrav-eled osteocyte functions. Osteocytes negatively regulate bone mass by stimulating os-teoclastogenesis and inhibiting osteoblast function in physiological condition. Osteo-cytes are responsible for bone loss in unloaded condition, and osteocytes augment theirfunctions by further stimulating osteoclastogenesis and further inhibiting osteoblastfunction, at least partly, through the upregulation of receptor activator of nuclear factor-kappa B ligand (RANKL) in osteoblasts and Sost in osteocytes in unloaded condition.
Abstract
Osteocytes establish an extensive intracellular and extracellular communication systemvia gap junction-coupled cell processes and canaliculi, through which cell processes passthroughout bone, and the communication system is extended to osteoblasts on thebone surface. To examine the osteocyte function, several mouse models were estab-lished. To ablate osteocytes, osteocytes death was induced by diphtheria toxin. However,any types of osteocyte death result in necrosis, because dying osteocytes are not phago-cytosed by scavengers. After the rupture of cytoplasmic membrane, immunostimulatorymolecules are released from lacunae to bone surface through canaliculi, and stimulatemacrophages. The stimulated macrophages produce interleukin (IL)-1, IL-6, and tumornecrosis factor-alpha (TNF- α), which are the most important proinflammatory cytokinestriggering inflammatory bone loss. Therefore, the osteocyte ablation results in necrosis-induced severe osteoporosis. In conditional knockout mice of gap junction protein al-pha-1 (GJA1), which encodes connexin 43 in Gap junction, using dentin matrix protein 1(DMP1) Cre transgenic mice, osteocyte apoptosis and enhanced bone resorption occur,because extracellular communication is intact. Overexpression of Bcl-2 in osteoblasts us-ing 2.3 kb collagen type I alpha1 (COL1A1) promoter causes osteocyte apoptosis due tothe severe reduction in the number of osteocyte processes, resulting in the disruption ofboth intracellular and extracellular communication systems. This mouse model unrav-eled osteocyte functions. Osteocytes negatively regulate bone mass by stimulating os-teoclastogenesis and inhibiting osteoblast function in physiological condition. Osteo-cytes are responsible for bone loss in unloaded condition, and osteocytes augment theirfunctions by further stimulating osteoclastogenesis and further inhibiting osteoblastfunction, at least partly, through the upregulation of receptor activator of nuclear factor-kappa B ligand (RANKL) in osteoblasts and Sost in osteocytes in unloaded condition.
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