Abstract
Bone metabolism is strictly regulated, and impaired regulation caused by hormonal imbalances induces systemic bone loss. Local bone loss caused by tumor invasion into bone is suggested to be induced by the generation of cytokines, which affect bone metabolism, by tumor cells. The major cause of systemic and local bone losses is excess bone resorption by osteoclasts, which differentiate from macrophages by receptor activator of nuclear factor kappa-B ligand (RANKL) or tumor necrosis factor-alpha (TNF-α). We previously found a novel pathway for tumor-induced osteoclastogenesis targeting osteoclast precursor cells (OPCs). Tumor-induced osteoclastogenesis was resistant to RANKL and TNF-α inhibitors. In the present study, we confirmed that exosomes derived from oral squamous cell carcinoma (OSCC) cells induced osteoclasts from OPCs. We also showed that the depletion of exosomes from culture supernatants of OSCC cells partially interfered with osteoclastogenesis, and cannabidiol, an innoxious cannabinoid without psychotropic effects, almost completely suppressed tumor-induced osteoclastogenesis. Osteoclastogenesis and its interference by cannabidiol were independent of the expression of nuclear factor of T cell c1 (NFATc1). These results show that osteoclastogenesis induced by OSCC cells targeting OPCs is a novel osteoclastogenic pathway independent of NFATc1 expression that is partially caused by tumor-derived exosomes and suppressed by cannabidiol.
Highlights
Reductions in bone volume induce osteopenia, which may lead to osteoporosis
We speculated that the targets for osteoclastogenesis induced by oral squamous cell carcinoma (OSCC) cells were not macrophages but osteoclast precursor cells (OPCs), which were already exposed to receptor activator of nuclear factor kappa-B ligand (RANKL) near the bone surface
We previously reported that OSCC cells induced osteoclasts from OPCs, which themselves do not have the capacity to differentiate into osteoclasts without further stimulation by RANKL or TNF-α [17]
Summary
Reductions in bone volume induce osteopenia, which may lead to osteoporosis. Osteopenia is caused by an imbalance in bone metabolism, and postmenopausal osteopenia/osteoporosis is attributed to excess bone resorption due to an estrogen deficiency [1]. TNF-α may induce osteoclasts and is regarded as another osteoclastogenic factor [3,4], but anti-bone resorptive effects of TNF-α have been considered through control of inflammation, and anti-TNF-α agents do not have any beneficial effect on interference of bone resorption [5]. Another major cause of pathological bone resorption occurs by metastasis or the direct invasion of malignant tumors into bone [6]. Parathyroid hormone-related peptide (PTHrP) is a well-known tumor-associated inducer of osteoclasts that stimulates the expression of RANKL [7]
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