Cannabinoid Receptors Regulation of Bone Mass, Bone Loss, and Osteoclastic Activity

The orexigenic endocannabinoids, arachidonoylethanolamide (anandamide) and 2-arachidonoylglycerol (2-AG) have been recently identified; they are eicosanoid derivatives of arachidonic acid from which prostaglandins and leukotrienes are also synthesized.^1-3 They interact with 2 cell membrane G-protein coupled receptors (CNR1 - OMIM 114610, chromosome 6q14-q15; CNR2 - OMIM 605051) to inhibit adenylyl cyclase and to stimulate intracellular mitogen-activated protein kinase signal transduction pathways in the central and peripheral nervous system, liver, and immune system. The endocannabinoid system increases appetite by central mechanisms and hepatic fatty acid synthesis directly. Studying CNR1^-/ “knock-out” mice, Idris and colleagues reported that endocannabinoids also regulate bone mineral density (BMD) by decreasing osteoclast activity. In CNR1^-/- mice, BMD was significantly increased relative to wild-type (WT) mice in the femur (+18%) and spine (+10%), primarily due to increased in trabecular volume, thickness, and number. Ovariectomy of CNR1^-/- female mice did not lead to reduced trabecular BMD as it did in WT ovariectomized, otherwise intact animals. Murine osteoclasts (but not osteoblasts) were demonstrated to express both CNR1 and CNR2. In vitro, CNR1 and CNR2 agonists and antagonists affected neither the growth nor viability of cultured osteoblasts. However, in vitro CNR1 and CNR2 antagonists inhibited osteoclast differentiation from cultured, isolated mononuclear cells derived from bone marrow, while receptor agonists stimulated osteoclast formation. In vivo administration of either a CNR1 or CNR2 antagonist prevented bone loss in ovariectomized WT mice. Microscopically, CNR1/CNR2 antagonists prevented the increase in osteoclast number that accompanies ovariectomy-induced bone loss while the number of osteoblasts was unaffected. Further in vitro studies demonstrated that CNR1 and CNR2 antagonists increased the rate of apoptosis of osteoclasts by activation of caspase 3. The investigators concluded that the endocannabinoids act through their CNR1 and CNR2 receptors to stimulate osteoclastogenesis. They suggested that excessive use of cannabis derivatives might lead to bone demineralization and that cannabinoid antagonists might be of therapeutic benefit in patients with osteoporosis of diverse pathogenesis.

Cannadinoid type 1 (CB 1) knockout (KO) mice are protected against ovariectomy-induced bone loss. (a) Total BMD at the tibial metaphysis in CB 1 KO mice and wild-type (WT) littermates before and after sham operation or ovariectomy (Ovx). (b) Bone volume/total volume assessed at the same site by microcomputed tomography. (c) Trabecular thickness assessed by microcomputed tomography. (d) Trabecular number assessed by µCT. Data are expresses as the percent change relative to the value in sham-operatied WT animals and are mean + s.e.m. ***P < 0.001, **P < 0.01, * P < 0.05, comparing CB 1 KO and WT mice.

Editor’s Comment : The appetite stimulating effects of products of the cannabis plant, primarily Δ⁹-tetrahydrocannabinol and related compounds, have long been recognized.^1-3 Anandamide and 2-AG are not stored but are synthesized and secreted as required. Inhibition of endocannabinoid action by antagonists of the CNR1 receptor or in “knock-out” models of CNR1-deficient mice leads to decreased food intake and resistance to diet-induced obesity. Endocannabinoids act both peripherally through the vagus nerve and centrally in the paraventricular and lateral hypothalamic nuclei (but not in the arcuate nuclei) to increase appetite and decrease energy utilization; they also act peripherally to increase lipogenesis.

An antagonist of CNR1 (rimonabant) that might also be useful in the management of low bone mass is currently in clinical trials for management of obesity. Leptin, an anorexigenic product of white adipocytes that also mediates energy utilization, and its cytokine-like receptor are expressed by human osteoblasts and, in vitro, enhances osteoblast differentiation, proliferation and collagen synthesis, thus promoting mineralization; leptin also inhibits both apoptosis of osteoblasts and osteoclast formation - the latter perhaps by increasing osteoprotegerin synthesis.⁴ Thus, leptin may be one of a number of mediators (mechanical strain, elevated estrogen and insulin levels) of the high bone mass that is present in obese subjects. However, administration of leptin into the cerebral ventricles inhibits bone formation, perhaps by triggering activation of the hypothalamic-pituitary-adrenocortical axis. Clearly, the observations that link endogenous factors that regulate appetite and energy utilization with bone mineralization merit further investigation.


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Current GGH - Vol. 24 No. 1 View table of contents Download PDF
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