The endovanilloid/endocannabinoid system: a new potential target for osteoporosis therapy.
Human osteoclasts express functional TRPV1 channels, CB1/CB2 cannabinoid receptors and endocannabinoid/endovanilloid synthetic/catabolic enzymes. Pharmacologic manipulation of this system can modulate osteoclast activity. Here, through multidisciplinary approaches, we demonstrate that enzymes and receptors of the endocannabinoid/endovanilloid system are differently expressed in osteoclasts from menopausal women without or with osteoporosis. We report that in osteoclasts from osteoporotic patients, TRPV1 channels are upregulated and, if persistently stimulated with resiniferatoxin, become clustered to the plasma membrane while inducing a massive over-expression of CB2 receptors. 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. Our data pave the way to the use of TRPV1 agonist together with CB2 agonists or CB1 antagonists in osteoporosis.
Department of Pediatrics, Second University of Naples, Naples, Italy. fra.rossi76@libero.it
Francesca
F
Rossi
Giulia
G
Bellini
Livio
L
Luongo
Marco
M
Torella
Silvia
S
Mancusi
Luciano
L
De Petrocellis
Stefania
S
Petrosino
Dario
D
Siniscalco
Pierangelo
P
Orlando
Mariantonietta
M
Scafuro
Nicola
N
Colacurci
Silverio
S
Perrotta
Bruno
B
Nobili
Vincenzo
V
Di Marzo
Sabatino
S
Maione
D000135:Acid Phosphatase / Q000378:metabolism; D000581:Amidohydrolases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D001842:Bone and Bones / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism*; D002452:Cell Count; D002478:Cells, Cultured; D063388:Endocannabinoids; D005260:Female; D005786:Gene Expression Regulation; D020868:Gene Silencing; D006801:Humans; D007150:Immunohistochemistry; D042541:Intracellular Space / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism; D008024:Ligands; D008049:Lipase / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010010:Osteoclasts / Q000201:enzymology / Q000473:pathology; D010024:Osteoporosis / Q000473:pathology / Q000628:therapy*; D010739:Phospholipase D / Q000235:genetics / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D017698:Postmenopause / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D050916:TRPV Cation Channels / Q000235:genetics / Q000378:metabolism*; D000071681:Tartrate-Resistant Acid Phosphatase; D000099252:Fatty Acid Amide Hydrolases
D000135:Acid Phosphatase; D000581:Amidohydrolases; D002118:Calcium; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D007527:Isoenzymes; D008024:Ligands; D008049:Lipase; D016328:NF-kappa B; D010739:Phospholipase D; D012333:RNA, Messenger; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D050916:TRPV Cation Channels; D000071681:Tartrate-Resistant Acid Phosphatase; D000099252:Fatty Acid Amide Hydrolases