J Bone Metab.  2014 Feb;21(1):55-60.

Mouse Models for the Evaluation of Osteocyte Functions

• Komori T

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.

Keyword

Bcl-2; Osteocyte; RANK ligand; Sost protein; Stress mechanical

MeSH Terms

Animals
Apoptosis
Bone Resorption
Cell Membrane
Collagen Type I
Connexin 43
Connexins
Cytokines
Dentin
Diphtheria Toxin
Gap Junctions
Interleukin-6
Interleukins
Macrophages
Mice*
Mice, Knockout
Mice, Transgenic
Necrosis
Osteoblasts
Osteocytes*
Osteoporosis
RANK Ligand
Rupture
Tumor Necrosis Factor-alpha
Up-Regulation
Collagen Type I
Connexin 43
Connexins
Cytokines
Diphtheria Toxin
Interleukin-6
Interleukins
RANK Ligand
Tumor Necrosis Factor-alpha

Figure

• 

  Fig. 1 Mouse models for the evaluation of osteocyte functions. (A) Massive osteocyte necrosis enhances osteoclastogenesis and inhibits bone formation by inhibiting osteoblast maturation, resulting in severe osteoporosis. The mouse model of osteocyte ablation shows the effects of massive necrosis of osteocytes. (B) In conditional gap junction protein alpha-1 (GJA1) knockout mice, low or moderate number of osteocytes die by apoptosis. After the rupture of the cytoplasmic membrane, immunostimulatory molecules are released and osteoclastogenesis is enhanced. The increased apoptosis is associated with the enhanced bone formation. (C) In Bcl-2 transgenic mice, massive osteocyte death occurs but immunostimulatory molecules are not released due to the severe reduction in the number of canaliculi. In Bcl-2 transgenic mice, osteoclastogenesis is inhibited and bone formation is enhanced.

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