Mouse Models for the Evaluation of Osteocyte Functions

ABSTRACT

Osteocytes establish an extensive intracellular and extracellular communication system via gap junction-coupled cell processes and canaliculi, through which cell processes pass throughout bone, and the communication system is extended to osteoblasts on the bone surface. To examine the osteocyte function, several mouse models were established. To ablate osteocytes, osteocytes death was induced by diphtheria toxin. However, any types of osteocyte death result in necrosis, because dying osteocytes are not phagocytosed by scavengers. After the rupture of cytoplasmic membrane, immunostimulatory molecules are released from lacunae to bone surface through canaliculi, and stimulate macrophages. The stimulated macrophages produce interleukin (IL)-1, IL-6, and tumor necrosis factor-alpha (TNF-alpha), which are the most important proinflammatory cytokines triggering inflammatory bone loss. Therefore, the osteocyte ablation results in necrosis-induced severe osteoporosis. In conditional knockout mice of gap junction protein alpha-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 using 2.3 kb collagen type I alpha1 (COL1A1) promoter causes osteocyte apoptosis due to the severe reduction in the number of osteocyte processes, resulting in the disruption of both intracellular and extracellular communication systems. This mouse model unraveled osteocyte functions. Osteocytes negatively regulate bone mass by stimulating osteoclastogenesis and inhibiting osteoblast function in physiological condition. Osteocytes are responsible for bone loss in unloaded condition, and osteocytes augment their functions by further stimulating osteoclastogenesis and further inhibiting osteoblast function, 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.