Melatonin, bone regulation and the ubiquitin-proteasome connection: A review

摘要

Recently, investigators have shown that ubiquitin-proteasome-mediated protein degradation is critical in regulating the balance between bone formation and bone resorption. The major signal transduction pathways regulating bone formation are the RANK/NF-kappa B pathway and the Wnt/beta-catenin pathway. These signal transduction pathways regulate the activity of mature osteoblasts and osteoclasts. In addition, the Wnt/beta-catenin pathway is one of the major signaling pathways in the differentiation of osteoblasts. The ubiquitin ligases that are reported to be of major significance in regulating these pathways are the ubiquitin SCFB-TrCP ligase (which regulates activation of NF-kappa B via degradation of IkB alpha in osteoclasts, and regulates bone transcription factors via degradation of beta-catenin), the Keap-Cul3-Rbx1 ligase (which regulates degradation of IkB kinase, Nrf2, and the antiapoptotic factor Bcl-2), and Smurf1. Also of significance in regulating osteoclastogenesis is the deubiquitinase, CYLD (cylindramatosis protein), which facilitates the separation of NF-kappa B from IkB alpha. The degradation of CYLD is also under the regulation of SCFB-TrCP. Proteasome inhibitors influence the activity of mature osteoblasts and osteoclasts, but also modulate the differentiation of precursor cells into osteoblasts. Preclinical studies show that melatonin also influences bone metabolism by stimulating bone growth and inhibiting osteoclast activity. These actions of melatonin could be interpreted as being mediated by the ubiquitin ligases SCFB-TrCP and Keap-Cul3-Rbx, or as an inhibitory effect on proteasomes. Clinical trials of the use of melatonin in the treatment of bone disease, including multiple myeloma, using both continuous and intermittent modes of administration, are warranted. (C) 2015 Elsevier Inc. All rights reserved.