Sci. Aging Knowl. Environ., 25 May 2005
Vol. 2005, Issue 21, p. nf39
[DOI: 10.1126/sageke.2005.21.nf39]


The Skeleton Goes to Pot

Prodding marijuana receptors spurs bone loss

R. John Davenport

In the kids' cartoon, slacker Shaggy and his canine sidekick Scooby Doo snarfed Scooby Snacks that, according to urban lore, contained a magic ingredient: marijuana. Maybe that's why Shaggy had bad posture. New results reveal that activating a marijuana receptor spurs bone loss, and obstructing it reinforces bone, at least in mice. If the findings hold up in people, receptor-blocking drugs--already in trials to battle obesity--might combat osteoporosis.

To freshen the skeleton, bone cells called osteoclasts dissolve tired bone, and other cells called osteoblasts rebuild it. But when osteoclasts outwork osteoblasts, bones thin, and osteoporosis results. Cues in the brain, such as the hormone leptin, can influence skeleton renovations (see "No Bones About It," "The Plot Thickens on Thin Bones," and "The Two Faces of Leptin"). Bone biologist Stuart Ralston of the University of Aberdeen in the U.K. and colleagues wondered whether other brain signals also mold bone. Cannabinoid receptors in the brain grab compounds in marijuana and also snag the body's related molecules, called endocannabinoids, causing the munchies and other physiological changes. Ralston had previously found that the neurotransmitter nitric oxide spurs osteoporosis, and some studies suggest that endocannabinoids prompt nitric oxide release, so his team investigated whether cannabinoids alter bone integrity.

The researchers studied mice that lack the gene for one cannabinoid receptor, CB1. The animals' femurs were about 18% denser than normal. Osteoporosis is prevalent in postmenopausal women, so the team removed the ovaries from female mice. In normal animals, this procedure dropped bone density by 40%. But in CB1-lacking mice, it had no effect. Similarly, compounds that obstruct cannabinoid receptors restored bone density when fed to normal animals without ovaries.

Next, the team exposed osteoblasts and osteoclasts to compounds that affect cannabinoid receptors. None influenced osteoblast growth or vitality. But substances that tied up the receptors crippled osteoclast multiplication, and compounds that activated receptors stimulated it. These cell-culture studies imply that receptors located on bone cells might influence the tissue, but they don't exclude a role for receptors in the brain, says Ralston. He adds that a receptor-blocking drug called rimonabant, which suppresses appetite, is undergoing final human tests for preventing obesity. "You would predict that it would protect against osteoporosis, too," he says. "It could be a blockbuster."

"It's a new bone-control mechanism," says bone researcher Gerard Karsenty of Baylor College of Medicine in Houston, Texas. Next, researchers must establish whether brain or bone receptors are key, he says. Cannabinoid researcher Aron Lichtman of Virginia Commonwealth University in Richmond says that they should also investigate whether recreational or medicinal marijuana users are prone to osteoporosis.

The relation between cannabinoid receptors and bone might not be straightforward, however. An Israeli team reported at meetings last year that removing a different receptor--CB2--accelerates bone loss. The two proteins appear in distinct tissues--CB1 mostly in brain and CB2 predominantly in immune cells--so those locational differences or differences in genetic background might underlie the discrepancy, says Lichtman. Further studies should reveal whether firing up pot receptors keeps bone density from getting high.

May 25, 2005
  1. A. I. Idris et al., Regulation of bone mass, bone loss and osteoclast activity by cannabinoid receptors. Nature Med., 22 May 2005 [e-pub ahead of print]. doi:10.1038/nm1255
  2. M. Karsak et al., The cannabinoid CB2 receptor: A potential target for the diagnosis and treatment of osteoporosis. Annual Meeting of the American Society for Bone and Mineral Research (2004). [Abstract]
Citation: R. J. Davenport, The Skeleton Goes to Pot. Sci. Aging Knowl. Environ. 2005 (21), nf39 (2005).

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