A Novel, Tumor-Induced Osteoclastogenesis Pathway Insensitive to Denosumab but Interfered by Cannabidiol

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.

IL-1 Generated by Oral Squamous Cell Carcinoma Stimulates Tumor-Induced and RANKL-Induced Osteoclastogenesis: A Possible Mechanism of Bone Resorption Induced by the Infiltration of Oral Squamous Cell Carcinoma

“…Histopathological findings of OSCC cases with in the bone reveal the interposition of fibrous stromal tissue between cancer c surfaces. Culture supernatants of OSCC cells revealed osteoclastogenesis w with OPCs, and we identified the cause as secreted vesicles or certain solu the previous study, we showed that extracellular microvesicles secreted fro that had osteoclastogenic properties induced osteoclastogenesis when suppl OPC cultures [28]. Notably, the depletion of extracellular microvesicles fro supernatant significantly decreased the osteoclastogenic activity, but not co Hence, to search for other candidates, we analyzed soluble factors secreted b Among numerous soluble factors, some inflammatory cytokines have b stimulate osteoclastogenesis [21].…”

“…Culture supernatants of OSCC cells revealed osteoclastogenesis when cultured with OPCs, and we identified the cause as secreted vesicles or certain soluble factors. In the previous study, we showed that extracellular microvesicles secreted from OSCC cells that had osteoclastogenic properties induced osteoclastogenesis when supplemented with OPC cultures [28]. Notably, the depletion of extracellular microvesicles from the culture supernatant significantly decreased the osteoclastogenic activity, but not completely [28].…”

“…However, they do not express any osteoclast functions and are unable to differentiate into osteoclasts without further stimulation by RANKL. Osteoclastogenesis induced by OSCC cells targeting OPCs was resistant to RANKL inhibitory agents, such as osteoprotegerin (OPG) and denosumab, in contrast to RANKL-induced osteoclastogenesis [27,28]. Furthermore, osteoclastogenesis induced by OSCC cells did not correlate with the upregulation of NFATc1 expression, and tumor-induced osteoclastogenesis, which targets OPCs, was caused by unknown mechanisms.…”

“…Furthermore, osteoclastogenesis induced by OSCC cells did not correlate with the upregulation of NFATc1 expression, and tumor-induced osteoclastogenesis, which targets OPCs, was caused by unknown mechanisms. Thereafter, we found that osteoclastogenesis induced by OSCC cells was partly caused by secreted extracellular microvesicles, and cannabidiol (CBD), one of the cannabinoids that does not express psychotomimetic functions, effectively attenuated osteoclastogenesis induced by OSCC cells and did not affect RANKL-induced osteoclastogenesis [28]. In this study, we aimed to clarify the unknown factors responsible for osteoclastogenesis induced by OSCC cells using a subclone of OSCC cells which did not have osteoclastogenic properties, selected IL-1 as a stimulator of both tumor-induced and RANKL-induced osteoclastogenesis, and examined the biological significance of IL-1 in bone resorption induced by OSCC.…”

Do E-cigarettes and vaping have a lower risk of osteoporosis, nonunion, and infection than tobacco smoking?

“… 54 , 55 There is also evidence that CBD can suppress osteoclastogenesis and reduce the function of human osteoclasts. 56 , 57 …”