Autophagy in mineralizing tissues: microenvironmental perspectives.
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.
Srinivas
Vickram
V
Department of Orthopaedic Surgery, Jefferson Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
Bohensky
Jolene
J
Zahm
Adam M
AM
Shapiro
Irving M
IM
D000263:Adenylate Kinase / Q000378:metabolism; D001343:Autophagy / Q000502:physiology*; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D001842:Bone and Bones / Q000166:cytology / Q000378:metabolism; D002113:Calcification, Physiologic; D002358:Cartilage, Articular / Q000166:cytology / Q000502:physiology; D019902:Chondrocytes / Q000166:cytology / Q000502:physiology*; D004777:Environment; D006132:Growth Plate / Q000166:cytology / Q000502:physiology; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D000099162:Endothelial PAS Domain-Containing Protein 1
D000263:Adenylate Kinase; D051792:Basic Helix-Loop-Helix Proteins; D051793:Hypoxia-Inducible Factor 1; D000099162:Endothelial PAS Domain-Containing Protein 1