1. Academic Validation
  2. Carnitine functions as an enhancer of NRF2 to inhibit osteoclastogenesis via regulating macrophage polarization in osteoporosis

Carnitine functions as an enhancer of NRF2 to inhibit osteoclastogenesis via regulating macrophage polarization in osteoporosis

  • Free Radic Biol Med. 2024 Jan 19:S0891-5849(24)00017-0. doi: 10.1016/j.freeradbiomed.2024.01.017.
Tao Yang 1 Shijie Liu 1 Haiwei Ma 1 Hehuan Lai 1 Chengdi Wang 1 Kainan Ni 1 Yahong Lu 1 Weiqing Li 1 Xingyu Hu 1 Zhiguo Zhou 1 Chao Lou 2 Dengwei He 3
Affiliations

Affiliations

  • 1 The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui Municipal Central Hospital, 289 Kuocang Road, Lishui, Zhejiang, 323000, PR China.
  • 2 The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui Municipal Central Hospital, 289 Kuocang Road, Lishui, Zhejiang, 323000, PR China. Electronic address: louchaoyisheng@163.com.
  • 3 The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui Municipal Central Hospital, 289 Kuocang Road, Lishui, Zhejiang, 323000, PR China. Electronic address: hedw120@zju.edu.cn.
Abstract

Osteoporosis, which manifests as reduced bone mass and deteriorated bone quality, is common in the elderly population. It is characterized by persistent elevation of macrophage-associated inflammation and active osteoclast bone resorption. Currently, the roles of intracellular metabolism in regulating these processes remain unclear. In this study, we initially performed bioinformatics analysis and observed a significant increase in the proportion of M1 macrophages in bone marrow with aging. Further metabolomics analysis demonstrated a notable reduction in the expression of carnitine metabolites in aged macrophages, while carnitine was not detected in osteoclasts. During the differentiation process, osteoclasts took up carnitine synthesized by macrophages to regulate their own activity. Mechanistically, carnitine enhanced the function of Nrf2 by inhibiting the Keap1-Nrf2 interaction, reducing the proteasome-dependent ubiquitination and degradation of Nrf2. In silico molecular ligand docking analysis of the interaction between carnitine and Keap1 showed that carnitine binds to Keap1 to stabilize Nrf2 and enhance its function. In this study, we found that the decrease in carnitine levels in aging macrophages causes overactivation of osteoclasts, ultimately leading to osteoporosis. A decrease in serum carnitine levels in patients with osteoporosis was found to have good diagnostic and predictive value. Moreover, supplementation with carnitine was shown to be effective in the treatment of osteoporosis.

Keywords

Carnitine; Keap1/Nrf2; M1 macrophage; Osteoclastogenesis; Osteoporosis; Ubiquitination.

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