Osteocyte apoptosis: the roles and key molecular mechanisms in resorption-related bone diseases

Abstract

Vital osteocytes have been well known to function as an important orchestrator in the preservation of robustness and fidelity of the bone remodeling process. Nevertheless, some key pathological factors, such as sex steroid deficiency and excess glucocorticoids, and so on, are implicated in inducing a bulk of apoptotic osteocytes, subsequently resulting in resorption-related bone loss. As much, osteocyte apoptosis, under homeostatic conditions, is in an optimal state of balance tightly controlled by pro- and anti-apoptotic mechanism pathways. Importantly, there exist many essential signaling proteins in the process of osteocyte apoptosis, which has a crucial role in maintaining a homeostatic environment. While increasing in vitro and in vivo studies have established, in part, key signaling pathways and cross-talk mechanism on osteocyte apoptosis, intrinsic and complex mechanism underlying osteocyte apoptosis occurs in various states of pathologies remains ill-defined. In this review, we discuss not only essential pro- and anti-apoptotic signaling pathways and key biomarkers involved in these key mechanisms under different pathological agents, but also the pivotal role of apoptotic osteocytes in osteoclastogenesis-triggered bone loss, hopefully shedding new light on the attractive and proper actions of pharmacotherapeutics of targeting apoptosis and ensuing resorption-related bone diseases such as osteoporosis and fragility fractures.

Fig. 1. Proposed model of the interplay between osteocyte apoptosis and autophagy.

Pro-apoptotic stimuli that stimulate death receptors and mitochondria-mediated apoptotic pathways give rise to the triggering of pro-survival autophagy-related biomarkers including Beclin-1 and BCL-2. In the process of continued exposure to apoptotic stimuli, phosphorylation of BCL-2, which separates from Beclin-1, translocates to mitochondria and sensitizes cells to apoptotic signals and blocks BCL-2 from suppressing pro-apoptotic biomarkers, thereby enhancing cells apoptosis. This demonstrates a mechanism of a positive-feedback loop for amplifying the death of cells.

Fig. 2. Key pro-apoptotic and anti-apoptotic pathways in osteocytes under different pathological conditions.

These signaling pathways, including pro-apoptotic pathways (red arrows) and anti-apoptotic pathways (green arrows), are closely related to increased bone resorption and decreased bone formation.

Fig. 3. The balance between pro- and anti-apoptotic pathways of osteocyte apoptosis.

Under physiological conditions, it is in an optimal state of balance tightly controlled by pro- and anti-apoptotic mechanism pathways. Once this balance is upset, masses of osteocytes may undergo apoptosis, thereby resulting in bone metabolism disorder.

Fig. 4. Model of anti-apoptotic signaling pathways in osteocytes.

Initiation of the mitogen-activated protein kinase (MAPK) cascade is triggered by key pathological agents including Es, FSS, and so on, thereby promoting cell survival. Besides, the cAMP/PKA pathway, Sema3A-Nrp1-sGC-cGMP pathway, PTHrP/PTH1R system, and VEGF/VEGFR2 system activation also functions as a cooperator during this process. Intriguingly, there exists a cross-talk mechanism among caveolin-1/ERKs signalings and Wnt/β-catenin signalings and PI3k/AKT signalings.

Fig. 5. Model of the role of osteocyte apoptosis in osteoclastogenesis-triggered bone loss.

The direct and indirect role of osteocyte apoptosis in osteoclastogenesis, eventually, results in increased bone loss and bone fragility. During sustained exposure to apoptotic stimuli, masses of osteocytes may undergo apoptosis, concomitant with the unleashing of the pro-inflammatory and pro-osteoclastogenic biomarkers from osteocytes and osteoclasts cytokines including RANKL, HMGB1, TNF-ɑ, IL-6, etc, which in turn promote osteocytic apoptosis by an amplifying loop mechanism.