Speakers
Description
Inhibition of CPT1C ameliorates osteoporosis by regulating αKG levels through interaction with OGDH
Zhong Xiaoyi1, #, Zhu Linlin1, #, Li Julin1, Fang Jian-Hong1, Zhou Yanying1, , Bi Huichang1, *
1 School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China.
Correspondence to: Huichang Bi, bihchang@smu.edu.cn
Background: Osteoporosis is characterized by suppressed osteoblastic function and enhanced osteoclastic activity. Alpha-ketoglutarate (αKG), an intermediate in the TCA cycle, is catabolized by oxoglutarate dehydrogenase (OGDH). Our previous study found that CPT1C was highly expressed in the femoral tissues of osteoporosis models. The current study aims to investigate the effect of CPT1C on osteoporosis.
Methods: A series of cell phenotype indicators, such as BrdU, colony formation, ALP and ARS staining were performed to clarify the effects of CPT1C and OGDH expression on osteoblast proliferation and differentiation. Ovariectomized C57BL/6 and Cpt1c⁻/⁻ mice were used to assess the effect of CPT1C on osteoporosis via micro-CT, H&E and IHC staining. αKG levels were detected using the ELISA kit. Immunofluorescence and Co-IP assays were employed to examine the interaction between CPT1C and OGDH. Dot blot and western blot assays were utilized to screen and clarify the impact of CPT1C silencing on histone trimethylation modifications.
Results: Knockdown of CPT1C markedly promoted osteoblast proliferation and differentiation. In vivo, AAV-mediated targeted knockdown of CPT1C or systemic CPT1C knockout significantly ameliorated mouse osteoporosis. αKG was found to be consumed during osteoblast differentiation. αKG supplementation enhanced osteoblast function. Mechanistically, CPT1C interacted with OGDH and thus regulated αKG levels via OGDH. OGDH overexpression reversed the promotion of osteoblast proliferation and differentiation induced by CPT1C knockdown in vitro. Ultimately, CPT1C silencing elevated the expression of αKG-dependent histone demethylase KDM5D, consequently decreasing H3K9me3 modification levels.
Conclusion: These results elucidate a novel mechanism whereby CPT1C modulates osteoblast function and osteoporosis through OGDH-mediated αKG metabolism. This study provides a theoretical basis for CPT1C as a potential therapeutic target for osteoporosis.
Acknowledgements: This work was supported by the Natural Science Foundation of China (U23A20535, 82025034, 82304603, 82504888).
