Abstract
Bone is a dynamic tissue, whose homeostasis is maintained by a fine balance between osteoclast (OC) and osteoblast (OB) activity. The endocannabinoid/endovanilloid (EC/EV) system’s receptors are the cannabinoid receptor type 1 (CB1), the cannabinoid receptor type 2 (CB2), and the transient receptor potential cation channel subfamily V member 1 (TRPV1). Their stimulation modulates bone formation and bone resorption. Bone diseases are very common worldwide. Osteoporosis is the principal cause of bone loss and it can be caused by several factors such as postmenopausal estrogen decrease, glucocorticoid (GC) treatments, iron overload, and chemotherapies. Studies have demonstrated that CB1 and TRPV1 stimulation exerts osteoclastogenic effects, whereas CB2 stimulation has an anti-osteoclastogenic role. Moreover, the EC/EV system has been demonstrated to have a role in cancer, favoring apoptosis and inhibiting cell proliferation. In particular, in bone cancer, the modulation of the EC/EV system not only reduces cell growth and enhances apoptosis but it also reduces cell invasion and bone pain in mouse models. Therefore, EC/EV receptors may be a useful pharmacological target in the prevention and treatment of bone diseases. More studies to better investigate the biochemical mechanisms underlining the EC/EV system effects in bone are needed, but the synthesis of hybrid molecules, targeting these receptors and capable of oppositely regulating bone homeostasis, seems to be a promising and encouraging prospective in bone disease management.
Highlights
Despite its rigidity, bone can be defined as an extremely dynamic organ, in a constant remodeling process by osteoblasts (OBs) and osteoclasts (OCs), key cells in maintaining bone homeostasis and in answering to mechanical stresses [1,2]
The endocannabinoid (EC) system is composed of endogenous cannabinoid ligands (anandamide (AEA) and 2-arachidonoylglycerol (2-AG)), their specific receptors, the cannabinoid receptor type 1 (CB1) and type 2 (CB2), and all the enzymes involved in their synthesis and degradation [9]
The CB1 receptor is more expressed in the central nervous system (CNS), whereas the cannabinoid receptor type 2 (CB2) receptor can be found predominantly in peripheral tissues [16], even though there is growing evidences indicating that it is present in the brain [17,18]
Summary
Bone can be defined as an extremely dynamic organ, in a constant remodeling process by osteoblasts (OBs) and osteoclasts (OCs), key cells in maintaining bone homeostasis and in answering to mechanical stresses [1,2]. The pharmacological modulation of these receptors contributes to the maintenance of bone mass by stimulating stromal cells and osteoblasts and by inhibiting monocytes and osteoclasts [25,26] (Figure 1). In 2005, Idris et al observed that selective agonists at CB2 receptor (HU308 and JWH-133) induce RANK-L-mediated osteoclast formation [35], while in 2008, Bab et al demonstrated that CB2-deficient mice have a normal phenotype at birth, but they undergo a bone mass reduction over time, suggesting a progressive age-related bone loss [37].
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