Wednesday, January 15, 2025
1/15/2025
PROJECT SUMMARY Longitudinal bone growth takes place in the growth plate (GP), where chondrocytes proliferate, synthesize extracellular matrix, and differentiate into hypertrophic chondrocytes. During puberty, the energy requirements of chondrocytes are increased due to their rapid proliferation and extensive matrix production, and inadequate energy supply as in malnutrition causes growth failure. Due to its avascular and hypoxic environment, it has been thought that the GP uses little lipids for fuel because lipid metabolism, such as fatty acid oxidation (FAO), requires oxygen. Instead, anaerobic glycolysis is thought to be the primary source of energy. On the other hand, diseases that affect lipid metabolism such as peroxisomal disorders and lipid storage disorders also cause short stature, raising the possibility that lipids may play an important role in the GP. However, lipid metabolism in the GP is poorly understood. Although the GP is avascular, it is flanked by two bone marrow cavities, and the upper and lower zones which are the resting and hypertrophic zones, respectively, are adjacent to blood vessels, suggesting that these zones have access to oxygen and nutrients in the circulating blood. Indeed, our preliminary studies have shown that the resting zone contains many lipid droplets (LDs). When fluorescently labeled lipids were injected intravenously, these lipids were observed in the resting zone within a few hours but disappeared within 24 hours, suggesting that chondrocytes in the resting zone actively capture and consume lipids from circulation. Consistently, lipidomic analysis of cultured primary chondrocytes detected Acyl-Carnitines, FA derivatives generated for FAO. Together with the recent finding that inhibition of mitochondrial oxidation in GP chondrocytes resulted in short limbs, these results suggest that GP chondrocytes are capable of utilizing lipids for energy production via FAO. In addition, we found that these chondrocytes containing LDs in the resting zone exclusively expressed Apolipoprotein E (ApoE), a lipid transporter. ApoE conditional knockout (KO) mice in chondrocytes had significantly shorter limbs. Lipidomic analysis of ApoE KO chondrocytes revealed altered lipid profiles compared to WT chondrocytes. These results suggest that ApoE endogenously expressed in chondrocytes plays an important role in bone growth and lipid metabolism. Therefore, we hypothesize that GP chondrocytes utilize lipids as an energy source and intrinsic ApoE in the resting chondrocytes mediates the initial lipid metabolism. This hypothesis will be addressed with the following Aims: (1) to determine whether the growth plate utilizes lipids as an energy source, (2) to identify the role of endogenous ApoE in the growth plate. Completion of these Aims will determine whether GP chondrocytes utilize FAO in vivo and whether this has biological significance. The outcome will revolutionize our understanding of energy metabolism in the GP.
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