Autophagy in mineralizing tissues: microenvironmental perspectives

Abstract

Chondrocytes in the growth plate and articular cartilage and osteocytes subsumed in Haversian bone exist in environmental niches that are characterized by a limited oxygen supply. In these tissues, cells display a hitherto unrecognized state in which there is evidence of autophagy. The autophagic condition serves to promote cell survival. When the response is triggered, the cell cannibalizes itself to generate energy; if extended, then it can activate Type II apoptosis. We opine that survival is dependent on niche conditions and regulated by crosstalk between mTOR, AMPK and HIF-1 and HIF-2. Recent studies suggest that HIF-2 is a potent regulator of chondrocyte autophagy and that this protein acts as a brake to the stimulatory function of HIF-1. Accordingly, the oxemic state of the tissue, its nutrient supply as well as the energetic state of the cells regulates autophagic flux. From a clinical viewpoint, it may be possible to enhance skeletal cell survival through drugs that modulate the autophagic state and prevent the induction of apoptosis.

Figure 1. Microenvironmental factors regulating autophagy on mineralizing cells

Under conditions of hypoxic stress, HIF-1 is stabilized leading to an energy charge dependent activation of AMPK. In addition, there is an increase in HIF-1 mediated REDD-1 expression. Thus, mTOR is inactivated resulting in a stimulation of autophagic flux. In parallel, an increase HIF-2 expression results in the dismutation of ROS, potent activators of autophagy. The reciprocal activities of HIF-1 and HIF-2 influence cell survival-death decisions.