Mitochondrial Dysfunction in Osteocytes Lacking the Growth Hormone Receptor

Presentation Number: SUN 467
Date of Presentation: April 2nd, 2017

Zhongbo Liu1, Maria De La Encarnacion Solesio Torregrosa1, Tianzhen Han2, Evgeny Pavlov3 and Shoshana Yakar*4
1New York University College of Dentistry New York, New York, 2New York University College of Dentistry, New York, NY, 3New York University College of Dentistry New York, NY, NY, 4New York University COLLEGE OF D, New York, NY

Abstract

Mitochondrial dysfunction has been recognized as a prominent feature of the diminishing cell function in aging bone. Studies of the long-lived growth hormone receptor knockout (GHRKO) mice, which show compromised skeletal growth, have suggested increased mitochondrial biogenesis and function in tissues, such as kidney, heart, and skin fibroblasts. The roles of GHR in maintaining mitochondrial function in osteocytes, the predominant population of bone cells, were not studied. Our goal was to understand the mechanisms by which GHRKO affects mitochondrial volume and function in the adult and aged bones. Using primary osteocyte cultures from 8 weeks old control and GHRKO mice we found that unlike in kidney and heart, in bone tissue of GHRKO mice despite ~40% decreases in osteocyte volume, mitochondrial volume remained the same at the level of ~20% of cell volume. Mitochondrial membrane potential (MMP) is a critical functional measure of mitochondria. Using tetramethylrhodamine ethyl ester, a potentiometric fluorescent probe, we found ~10% decreases in MMP in osteocytes from GHRKO when compared to osteocytes from control mice, suggesting decreased mitochondrial function with ablation of GHR. To further investigate the changes in mitochondrial function we measured the redox state of the mitochondrial NAD+/NADH pair. We found that GHRKO osteocytes show reduced NADH redox index compared to controls, indicating that the overall levels of NADH in the cell reduced. This suggests reduced TCA cycle activity. The impaired mitochondrial function was further confirmed by assay of cellular respiration. We found that GHRKO osteocytes show reduced oxygen consumption rate as compared to controls, and reduced mitochondrial reserve capacity. This data together with decreased MMP and NADH levels, establish that mitochondrial function is compromised in the absence of GHR in osteocytes.

 

Nothing to Disclose: ZL, MD, TH, EP, SY