Table 2 Key pathological factors that are involved in the osteocyte apoptosis and their potential role.

Aging

Disruption of the Cx43/miR21 pathway; overproduction of ROS; induction of mitochondrial senescence and DNA damage

BAX, ROS, cyt C, NOXA, P53, P21

miR21, AMPK, PGC-1α, Atg7, LC3II, Beclin-1

Unloading/disuse

Generation of the senescence-associated secretory phenotype(SASP); upregulation of sclerostin to inhibit WNT/β-catenin signaling; disruption of LCN and increased localized hypoxia; overproduction of ROS

BNIP3, ROS, HIF-1α, NOX1, NOX2, Sclerostin, BAD

β1-integrin, FAK, NO, AMPK, Irisin, PGC-1α, Beclin-1, BCL-2, ORP150, PGE2, FGF7, LC3II, Cx43

Fatigue/microdamage

Rupture of dendritic processes; destroy of Cx43 gap; plasma membrane disruptions; upregulation of cellular communication network; upregulation of CCN2 through ERK1/2 pathway

HIF-1, ROS, NOX1, NOX2, Caspase-3, BAD, BAX, CCN2

FAK, c-fos, AMPK, PGC-1α, LC3II, caveolin-1, β1-integrin, Beclin-1, PGE2, Cx43, BCL-2

Estrogen/androgen deficiency

Overproduction of ROS; activation of autophagy pathway; activation of MAPK-dependent antioxidant signaling; elevation of iNOS and eNOS expression; activation of Sema3A-sGC-cGMP signalings

BAD, ROS, NOXA, P53, P66

Sema3A, AMPK, PGC-1α, NO, AKT, Beclin-1, LC3II, PI3K, RSK2

Excess glucocorticoids

Degeneration of the osteocyte LCN; upregulation of sclerostin to inhibit WNT/β-catenin signaling; activation of FAS/CD95 signalings pathway; stimulation of PTH signalings and autophagy pathway

ROS, NOX1, NOX2, CD95, Pyk2, JNK, Sclerostin, RANKL, DMP-1, CTSK, Caspases-3, -7, -8

AMPK, PGC-1α, caveolin-1, LC3II, Beclin-1, PGE2, PI3K, AKT, Cx43, caveolin-1, BCL-2

Inflammation

Unleashment of the bulk of pro-inflammatory cytokines by a positive-feedback loop; enhancement of oxidative stress; activation of AGEs/RAGE pathway

HMGB1, ROS, NOX1, NOX2, NF-κB, AP-1, CREB, STAT3, NFAT, TNF-α, IL-1β, IL-6, IL-18, VEGF-A, Caspase-1

CD40, AMPK, PGC-1α, Beclin-1, LC3II