Expression of the melatonin receptor (MT) 1 in benign and malignant human bone tumors

Abstract

The beneficial effects of melatonin on bone homeostasis have been shown in various diseases. As this indoleamine causes dose-dependent modulation of bone-forming osteoblast and bone-resorbing osteoclast activities by receptor-independent and -dependent pathways, we investigated the expression of G-protein-coupled melatonin receptors (MTs) in malignant and non-malignant human bone lesions. By TaqMan polymerase chain reaction (PCR), we analyzed 30 specimens from osteosarcoma and 11 from benign bone tumors for MT1-mRNA expression. Furthermore, we determined mRNA expression levels of the osteoclast activity-stimulating receptor activator of nuclear factor-kappa B ligand (RANKL) and its counterpart osteoprotegerin (OPG). Although mean MT1-mRNA levels were similar (P = 0.596) in malignant (4.39 +/- 4.98-fold) and benign samples (4.64 +/- 6.81-fold), the highest MT1-mRNA levels (up to 27-fold) were observed in individual osteosarcomas, particularly, in two specimens of patients with local recurrence of the tumor. Moreover, mean RANKL- and OPG-mRNA levels were similar in malignant and benign specimens (RANKL: 7.38 +/- 9.61-fold versus 3.57 +/- 3.11-fold, P = 0.207; OPG: 23.45 +/- 32.76 versus 8.07 +/- 7.23-fold, P = 0.133). Again, highest RANKL- and OPG-mRNA levels (up to 41- and 160-fold, respectively) were observed in individual osteosarcomas. Expression of MT1-mRNA was confirmed in two human osteosarcoma cell lines (HOS, MG63). High expression levels of MT1-mRNA together with low OPG-mRNA were found in both osteosarcoma cell lines, while in normal human osteoblasts and bone marrow stromal cells, high OPG-mRNA levels were associated with low MT1-mRNA levels. These data on the abundant expression of MT1-mRNA in human bone tumors and osteosarcoma cells lines suggest an important role for MT1 in bone pathology.

Paracrine-mediated osteoclastogenesis by the osteosarcoma MG63 cell line: is RANKL/RANK signalling really important?

“…However, expression of RANKL was very low, which is in agreement with previous studies that reported low expression levels of that molecule by MG63 cell line, assessed both by RT-PCR and qPCR [20][21][22][23][24]. In addition, in one of such reports the soluble form of RANKL was not detected on MG63 conditioned medium [21].…”

“…In addition, in one of such reports the soluble form of RANKL was not detected on MG63 conditioned medium [21]. It was proposed that RANKL expression is inversely related to the degree of osteoblastic differentiation [24] and it has been suggested that MG63 cells are osteoblast-like cells that exhibit several characteristics typical of comparatively immature osteoblasts [21].…”

“…In this context, the aim of the present work was to characterize the osteoclastogenic effects induced by the human MG63 osteosarcoma cell line through paracrine mechanisms. This cell line was selected because MG63 cells are believed to be relatively immature osteoblast-like cells [19] and are known to express low amounts of RANKL [20][21][22][23][24]. Both are relevant issues, as the modulation of osteoclastogenesis by osteoblasts is reported to be dependent on the degree of osteoblast differentiation [25] and RANKL is a key player in this process [3,5].…”

An insight into the scientific background and future perspectives for the potential uses of melatonin

“…High expression levels of MT1-mRNA together with low OPG-mRNA were found in both osteosarcoma cell lines, while in normal human osteoblasts and bone marrow stromal cells, high OPGmRNA levels were associated with low MT1-mRNA levels. These data on the abundant expression of MT1-mRNA in human bone tumors and osteosarcoma cells lines suggest an important role for MT1 in bone pathology [65]. Recently, one study investigated the effect of melatonin on proliferation of human osteosarcoma cell line MG-63 wherein they reported that melatonin significantly inhibit human osteosarcoma cell proliferation in a dose-dependent and time-dependent manner and this inhibition involves the downregulation of cyclin D1, CDK4, cyclin B1 and CDK1 [66].…”

LINE-1 activity as molecular basis for genomic instability associated with light exposure at night

“…[53][54][55][56][57] The levels of melatonin receptor expression vary significantly between normal and cancer cells, with most cancers expressing higher (and only a few lower) levels of the MT1 receptor than their corresponding normal tissues. [58][59][60][61][62] This suggests that cancer cells may be hypersensitive to melatonin suppression relative to their normal counterparts. The tissue-specific differences in the levels of melatonin receptor expression 61 suggest a possibility that various tissues may be experiencing different levels of upregulation in L1-induced damage upon LAN.…”