ABSTRACT
Title
The endovanilloid/endocannabinoid system: a new potential target for osteoporosis therapy
Authors
F. Rossi1, G. Bellini2, L. Luongo2, M. Torella3, S. Mancusi1,2, L. De Petrocellis4, D. Siniscalco2, S. Perrotta1, B. Nobili1, V. Di Marzo4, S. Maione2.
1 Dept. of Pediatrics, Second University of Naples, Italy
2 Dept. of Experimental Medicine, Second University of Naples, Italy
3 Dept. of Gynecology, Obstetrics and Reproductive Sciences, Second University of Naples, Italy
4 Institute of Biomolecular Chemistry, Institute of Cybernetics and Institute of Protein Biochemistry, National Research Council (CNR), Italy
1 Dept. of Pediatrics, Second University of Naples, Italy
2 Dept. of Experimental Medicine, Second University of Naples, Italy
3 Dept. of Gynecology, Obstetrics and Reproductive Sciences, Second University of Naples, Italy
4 Institute of Biomolecular Chemistry, Institute of Cybernetics and Institute of Protein Biochemistry, National Research Council (CNR), Italy
Abstract
Bone is a highly metabolically active tissue and its formation and resorption is at the base of bone remodelling, which continues throughout life. It is generally recognized that removal of bone is the task of osteoclasts (OCs), while its neo-formation relies on osteoblasts [1]. The critical importance of a balanced bone remodelling is demonstrated by human diseases, i.e. osteoporosis, in which a net increase in bone resorption is responsible of skeleton weakening and fracture risk [2].
Human osteoclasts express functional TRPV1 channels, CB1/CB2 cannabinoid receptors and
endocannabinoid/endovanilloid (EC/EV) synthetic/catabolic enzymes. Pharmacologic manipulation of this system can modulate osteoclast activity [3].
In this study, through multidisciplinary approaches, we demonstrate that enzymes and receptors of the EC/EV system are differently expressed in osteoclasts from menopausal women without or with osteoporosis. Overall, in osteoclasts from osteoporotic patients, TRPV1 channels are up-regulated and, if persistently stimulated with resiniferatoxin (RTX), become clustered to the plasma membrane whilst inducing a massive over-expression of CB2 receptors, the counterpart receptor system for bone mineralization and remodelling via osteoclast inhibition.
Accordingly, treatment with the CB2 agonist JWH-133 [5 μM] is able to induce a reduction of TRAP levels in menopausal healthy and osteoporotic OCs. Moreover, TRPV1 silencing is able to significantly reduce TRAP expression in osteoporotic OCs, whereas the non-targeting siRNA control is ineffective, and treatment with the vanilloid antagonist I-RTX [2.5 μM]modulates TRAP expression only in cells treated with the non-targeting siRNA control.
By providing new evidence for a critical functional cross-talk between CB2 and TRPV1 receptors in osteoporosis, we speculate that TRPV1 desensitization, or its enhanced trafficking, together with TRPV1 agonist-induced CB2 receptor overexpression, might be critical to minimize calcium entry in osteoclasts, which could be in turn responsible of cell over-activation and higher bone resorption.
In this direction, drug cocktails or hybrid molecules, designed to simultaneously stimulate CB2 receptors and activate/desensitize or antagonize TRPV1 channels, may prove useful in pathological conditions where an unbalanced osteoblast/osteoclast activity is observed. Our data pave the way to the use of TRPV1 agonist together with CB2 agonists in osteoporosis [4].
[1] Datta et al. (2008) The cell biology of bone metabolism. J Clin Pathol. 61:577–87.
[2] Teitelbaum (2000) Bone resorption by osteoclast. Science. 289:1504–8.
[3] Rossi et al. (2009) The endovanilloid/endocannabinoid system in human osteoclasts: possible involvement in bone formation and resorption. Bone. 44:476-84.
[4] Rossi et al. (2011) The endovanilloid/endocannabinoid system: A potential target for osteoporosis therapy. Bone in press.
Human osteoclasts express functional TRPV1 channels, CB1/CB2 cannabinoid receptors and
endocannabinoid/endovanilloid (EC/EV) synthetic/catabolic enzymes. Pharmacologic manipulation of this system can modulate osteoclast activity [3].
In this study, through multidisciplinary approaches, we demonstrate that enzymes and receptors of the EC/EV system are differently expressed in osteoclasts from menopausal women without or with osteoporosis. Overall, in osteoclasts from osteoporotic patients, TRPV1 channels are up-regulated and, if persistently stimulated with resiniferatoxin (RTX), become clustered to the plasma membrane whilst inducing a massive over-expression of CB2 receptors, the counterpart receptor system for bone mineralization and remodelling via osteoclast inhibition.
Accordingly, treatment with the CB2 agonist JWH-133 [5 μM] is able to induce a reduction of TRAP levels in menopausal healthy and osteoporotic OCs. Moreover, TRPV1 silencing is able to significantly reduce TRAP expression in osteoporotic OCs, whereas the non-targeting siRNA control is ineffective, and treatment with the vanilloid antagonist I-RTX [2.5 μM]modulates TRAP expression only in cells treated with the non-targeting siRNA control.
By providing new evidence for a critical functional cross-talk between CB2 and TRPV1 receptors in osteoporosis, we speculate that TRPV1 desensitization, or its enhanced trafficking, together with TRPV1 agonist-induced CB2 receptor overexpression, might be critical to minimize calcium entry in osteoclasts, which could be in turn responsible of cell over-activation and higher bone resorption.
In this direction, drug cocktails or hybrid molecules, designed to simultaneously stimulate CB2 receptors and activate/desensitize or antagonize TRPV1 channels, may prove useful in pathological conditions where an unbalanced osteoblast/osteoclast activity is observed. Our data pave the way to the use of TRPV1 agonist together with CB2 agonists in osteoporosis [4].
[1] Datta et al. (2008) The cell biology of bone metabolism. J Clin Pathol. 61:577–87.
[2] Teitelbaum (2000) Bone resorption by osteoclast. Science. 289:1504–8.
[3] Rossi et al. (2009) The endovanilloid/endocannabinoid system in human osteoclasts: possible involvement in bone formation and resorption. Bone. 44:476-84.
[4] Rossi et al. (2011) The endovanilloid/endocannabinoid system: A potential target for osteoporosis therapy. Bone in press.