title: Melatonin, bone regulation and the ubiquitin-proteasome connection: A review.
abstract: 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-κB pathway and the Wnt/β-catenin pathway. These signal transduction pathways regulate the activity of mature osteoblasts and osteoclasts. In addition, the Wnt/β-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 SCF(B-TrCP) ligase (which regulates activation of NF-κB via degradation of IkBα in osteoclasts, and regulates bone transcription factors via degradation of β-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-κB from IkBα. The degradation of CYLD is also under the regulation of SCF(B-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 SCF(B-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.
authors.affiliation: Department of Human Anatomy and Cell Science, University of Manitoba, 745 Bannatyne Avenue, Winnipeg, Manitoba R3E 0W3, Canada. Electronic address: Vriend@ms.umanitoba.ca.
authors.forename: Jerry
authors.initials: J
authors.lastname: Vriend
authors.affiliation: Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, TX, USA.
authors.forename: Russel J
authors.initials: RJ
authors.lastname: Reiter
mesh_terms: D000818:Animals; D001847:Bone Diseases / Q000378:metabolism / Q000473:pathology; D001862:Bone Resorption / Q000378:metabolism*; D001842:Bone and Bones / Q000378:metabolism / Q000473:pathology; D002940:Circadian Rhythm; D006801:Humans; D008550:Melatonin / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D010012:Osteogenesis; D010281:Parathyroid Hormone / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D053245:RANK Ligand / Q000378:metabolism; D044843:SKP Cullin F-Box Protein Ligases / Q000378:metabolism; D015398:Signal Transduction; D025801:Ubiquitin / Q000378:metabolism*
chemical_list: D016328:NF-kappa B; D010281:Parathyroid Hormone; D053245:RANK Ligand; D025801:Ubiquitin; D044843:SKP Cullin F-Box Protein Ligases; D046988:Proteasome Endopeptidase Complex; D008550:Melatonin
keywords: Bortezomib; Bortezomib (PubChem CID: 387447); Lactacystin (PubChem CID: 6610292); Melatonin (PubChem CID: 896); Osteoblasts; Osteoclasts; Parathyroid hormone; Rankl; SCF(B-TrCP)