Archive for the ‘osteoporosis’ Category

A number of recent preclinical studies have demonstrated the potential role of cannabinoids and their receptors in bone metabolism. Pharmacological and genetic modulation of cannabinoid receptors indicate that cannabinoid ligands may provide attractive and novel agents for the treatment of bone diseases. This article reviews the role of cannabinoid receptors in regulating bone mass, bone loss and bone cell function in health and disease. The article also provides support to the notion that cannabinoid receptor ligands show a great promise in the treatment of bone diseases associated with accelerated osteoclastic bone resorption including osteoporosis, rheumatoid arthritis and bone metastasis. Copyright 2008 Prous Science, S.A.U. or its licensors. All rights reserved.

Oral administration of ajulemic acid (AjA), a cannabinoid acid devoid of psychoactivity, prevents joint tissue injury in rats with adjuvant induced arthritis. Because activation of osteoclasts is central to the pathogenesis of bone erosion in patients with rheumatoid arthritis (RA), we investigated the influence of AjA on osteoclast differentiation and survival. Osteoclast cultures were established by stimulation of RAW264.7 cells and primary mouse bone marrow cultures with receptor activator of NF-kappaB ligand (RANKL). Simultaneous addition of AjA (15 and 30 microM) and RANKL to both culture systems significantly suppressed development of multinucleated osteoclasts (osteoclastogenesis) in a dose dependent manner, as determined by quantification of multinuclear, tartrate-resistant acid phosphatase (TRAP)-positive cells. AjA impaired growth of RAW264.7 monocytes and prevented further osteoclast formation in cultures in which osteoclastogenesis had already begun. Reduction by AjA of both monocyte growth and osteoclast formation was associated with apoptosis, assayed by annexin V and propidium iodide staining, and caspase activity. The anti-osteoclastogenic effects of AjA did not require the continuous presence of AjA in the cell cultures. Based on these findings, we propose that AjA or other nonpsychoactive synthetic analogs of Cannabis constituents may be useful therapy for diseases such as RA and osteoporosis in which bone resorption is a central feature. (c) 2007 Wiley-Liss, Inc.

Cannabidiol (CBD) is a cannabinoid component from Cannabis sativa that does not induce psychotomimetic effects and possess anti-inflammatory properties. In the present study we tested the effects of CBD in a periodontitis experimental model in rats. We also investigated possible mechanisms underlying these effects. Periodontal disease was induced by a ligature placed around the mandible first molars of each animal. Male Wistar rats were divided into 3 groups: control animals; ligature-induced animals treated with vehicle and ligature-induced animals treated with CBD (5 mg/kg, daily). Thirty days after the induction of periodontal disease the animals were sacrificed and mandibles and gingival tissues removed for further analysis. Morphometrical analysis of alveolar bone loss demonstrated that CBD-treated animals presented a decreased alveolar bone loss and a lower expression of the activator of nuclear factor-kappaB ligand RANKL/RANK. Moreover, gingival tissues from the CBD-treated group showed decreased neutrophil migration (MPO assay) associated with lower interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha production. These results indicate that CBD may be useful to control bone resorption during progression of experimental periodontitis in rats.

The active component of marijuana, Delta(9)-tetrahydrocannabinol, activates the CB1 and CB2 cannabinoid receptors, thus mimicking the action of endogenous cannabinoids. CB1 is predominantly neuronal and mediates the cannabinoid psychotropic effects. CB2 is predominantly expressed in peripheral tissues, mainly in pathological conditions. So far the main endocannabinoids, anandamide and 2-arachidonoylglycerol, have been found in bone at ‘brain’ levels. The CB1 receptor is present mainly in skeletal sympathetic nerve terminals, thus regulating the adrenergic tonic restrain of bone formation. CB2 is expressed in osteoblasts and osteoclasts, stimulates bone formation, and inhibits bone resorption. Because low bone mass is the only spontaneous phenotype so far reported in CB2 mutant mice, it appears that the main physiologic involvement of CB2 is associated with maintaining bone remodeling at balance, thus protecting the skeleton against age-related bone loss. Indeed, in humans, polymorphisms in CNR2, the gene encoding CB2, are strongly associated with postmenopausal osteoporosis. Preclinical studies have shown that a synthetic CB2-specific agonist rescues ovariectomy-induced bone loss. Taken together, the reports on cannabinoid receptors in mice and humans pave the way for the development of 1) diagnostic measures to identify osteoporosis-susceptible polymorphisms in CNR2, and 2) cannabinoid drugs to combat osteoporosis.

The study found that while the drug may reduce bone strength in the young, it could protect against osteoporosis, a weakening of the bones, in later life.

The results were uncovered by a team at the University of Edinburgh who compared the drug’s effects on mice.

Osteoporosis affects up to 30% of women and about 12% of men at some point in their lives.

The group found that cannabis can activate a molecule found naturally in the body that is key to the development of osteoporosis.

When the type 1 cannabinoid receptor (CB1) comes into contact with cannabis, it has an impact on bone regeneration.

However, until now, it was not clear whether the drug had a positive or negative effect.

‘Early results’

Researchers, funded by the Arthritis Research Campaign, investigated this using mice which lacked the CB1 receptor.

The scientists then used compounds – similar to those in cannabis – that activated the CB1 receptor.

They found that compounds increased the rate at which bone tissue was destroyed in the young.

Despite this, the study also showed that the same compounds decreased bone loss in older mice and prevented the accumulation of fat in the bones, which is known to occur in humans with osteoporosis.

Stuart Ralston, the Arthritis Research Campaign Professor of Rheumatology at the University of Edinburgh, who led the study, said: “This is an exciting step forward, but we must recognise that these are early results and more tests are needed on the effects of cannabis in humans to determine how the effects differ with age in people.

“We plan to conduct further trials soon and hope the results will help to deliver new treatments that will be of value in the fight against osteoporosis.”

The results are published in Cell Metabolism.