Table 1 Key biomarkers and their potential role in osteocytic pro- and anti-apoptotic signaling mechanisms.

Pro-apoptotic function

ROS

Generate the initial insult on mitochondria; induce either apoptosis or senescence; decrease bone mass and accelerate aging; increase degeneration of the osteocyte LCN^{24,25,48,72,109}

BAX

Target the mitochondria; induce rapid release of cyt C; accelerate the caspase cascade^49,66

PUMA

Target the mitochondria; induce rapid release of cyt C; accelerate the caspase cascade⁴⁹

Hcy

Increase the expressions of Nox; induce DNA damage⁹⁶

HMGB1

Trigger the generation of pro-inflammatory and pro-osteoclastic factors via positive feedback loop^{109,110,111,112,114}

FADD

Trigger a caspase cascade; induce GCs-induced apoptosis^6,118

Sclerostin

Promote osteocyte cells death upon unloading; inhibit bone formation^53,107,108

BNIP3

Promote cell death during hypoxia^60,62

CCN2

Promote osteocyte apoptosis upon excess mechanical stress^33,69

TNF-α

Stimulate osteocyte apoptosis upon inflammation and cancer^92,115,116

Caspase-3

Regulate osteocyte apoptosis via physical interactions in mechanistic stimulus^27,127

CTSK

Breakdown the bone matrix adjacent to the osteocyte; increase the size of the osteocyte lacunae and mineralization decrease vitality of osteocytes²³

DMP-1

Regulate osteocyte formation and phosphate homeostasis; involve in osteocytic apoptosis^29,84,154

Pyk2

Promote GCs-induced osteocytic apoptosis via focal adhesion⁸²

Panx-1

Promote fatigue-induced osteocytic apoptosis¹⁶⁰

Anti-apoptotic function

SOD2

Suppress aging and loss of bone mass; decrease degeneration of the osteocyte LCN^24,61

AMPK

Protects against Hcy-induced osteocyte apoptosis^96,101,102

NO

Maintain osteocytic vitality by pulsatile fluid flow^44,54,100

Cx43

Involve in gap junction; maintain intercellular communication and mechanical response^42,43,158

Beclin-1

Inhibit the oxidative stress; protect the survival of osteocytes^21,22,23,27

LC3

Inhibit the oxidative stress; protect the survival of osteocytes^21,22,23,28

PTH

Reverse the osteocyte apoptosis; promote gap junction-mediated intercellular coupling; stimulate Ca⁺² influx^{133,134,135,137}

VEGF

Couple angiogenesis and osteogenesis; preserve osteocytic vitality^140,141

β1-integrin

Regulate stretch-induced ERK activation; preserve osteocytic vitality⁹³

Caveolin-1

Involve in mechanotransduction in osteocytes⁵⁵

PGE2

Maintain osteocytic mechanotransduction upon unloading; block GCs-induced apoptosis⁵⁶

PI3K

Trigger the phosphorylation and inactivate the pro-apoptotic protein; preserve osteocytic vitality⁸²

Sema3A

Inhibit osteoclastic bone resorption and promote bone formation; regulate the survival of mature osteocytes; maintain bone mass in an estrogen-dependent manner⁷⁷

FGF7

Increase Cx43 expression; promote gap junction elongate; maintain the survival of osteocytes⁵⁹

Irisin

Prevent apoptosis of osteocytes through excise^57,58,91

CD40

Block TNF-α or GCs-induced osteocytic apoptosis⁹²

NAC

Alleviate estrogen/androgen deficiency-induced osteocyte apoptosis⁴⁸

CCL7

Promote bone formation; maintain osteocytic mechanotransduction; protect from GCs-induced osteocytic apoptosis⁸³

BCL-2

Suppress osteocytic apoptosis upon unloading/disuse and fatigue⁶⁶