Melatonin inhibits nucleus pulposus ( NP ) cell proliferation and extracellular matrix ( ECM ) remodeling via the melatonin membrane receptors mediated PI 3K‐Akt pathway

Pinealectomy in vertebrates accelerated intervertebral disk degeneration ( IDD ). However, the potential mechanisms, particularly melatonin's role, are still to be clarified. In this study, for first time, melatonin membrane receptors of MT 1 and MT 2 were found to be present in the human intervertebral disk tissues and nucleus pulposus ( NP ) cells, respectively. Melatonin treatment significantly inhibited NP cell proliferation in dose‐dependent manner. Accordingly, melatonin down‐regulated gene expression of cyclin D1, PCNA , matrix metallopeptidase‐3, and matrix metallopeptidase‐9 and upregulated gene expression of collagen type II alpha 1 chain and aggrecan in NP cells. These effects of melatonin were blocked by luzindole, a nonspecific melatonin membrane receptor antagonist. Signaling pathway analysis indicated that in the intervertebral disk tissues and NP cells, melatonin acted on MT 1/2 and subsequently reduced phosphorylation of phosphoinositide 3‐kinase p85 regulatory subunit, phosphoinositide‐dependent kinase‐1, and Akt. The results indicate that melatonin is a crucial regulator of NP cell function and plays a vital role in prevention of IDD .