February 23, 2009

New Mediator of Bone Breakdown Discovered

Photo of a microscope image of cell tunneling through bone matrix, leaving a black trail An osteoclast (outlined in pink) degrading bone (green and yellow). Ingested bone matrix appears as pale blue spots.Steve Nesbitt. All rights reserved by Wellcome Images.

Scientists have discovered a lipid mediator in blood that plays a key role in maintaining the balance between the build-up and breakdown of bone. Targeting this mediator may prove useful for treating bone degenerative diseases such as osteoporosis and rheumatoid arthritis.

Our bones are continuously being remodeled. There is a delicate balance between bone-forming cells called osteoblasts and bone-absorbing cells called osteoclasts. Working together, these cells repair fractures, release calcium and phosphate into the blood, and maintain overall bone structure. When this balance, or homeostasis, is tipped, it can lead to the bone loss of osteoporosis or inappropriate bone formation. Bone homeostasis is tightly regulated, but as we age, osteoclasts begin to outnumber osteoblasts and cause osteoporosis, which affects 44 million people nationwide, 68% of whom are women.

Osteoclasts are large cells uniquely designed to reabsorb bone. Immature osteoclasts migrate to the surface of the bones, where they can be activated to become mature osteoclasts. Only mature osteoclasts can degrade bone.

Recent studies have revealed unexpected connections between the skeletal and immune systems. Bone marrow houses stem cells important for replenishing the immune system. Conversely, immune cells release signaling molecules that affect bone structure. A team led by immunologist Dr. Ronald Germain at NIH’s National Institute of Allergy and Infectious Diseases (NIAID) and Dr. Masaru Ishii, a visiting fellow from Osaka University in Japan, examined the relationship between the immune system and the recruitment of osteoclasts to the bone surface.

The researchers focused on sphingosine-1-phosphate (S1P), a lipid in blood that’s known to direct the movement of immune cells with S1P receptors out of lymph nodes. Osteoclasts are derived from the same parent stem cells that give rise to these immune cells, making S1P a good candidate for controlling osteoclast migration.

In the online edition of Nature on February 8, 2009, the researchers reported that osteoclasts express S1P receptors on their surface. They also migrate toward S1P in the laboratory. The researchers next used an imaging technique called 2-photon excitation microscopy to image bone tissue in a live mouse. Adding drugs into blood that activate the S1P receptor, they found, caused immature osteoclasts to migrate away from bone.

To verify whether S1P is involved in bone metabolism, the scientists compared the bone density of mice with osteoclasts lacking the S1P receptor to normal mice. Mice missing the receptor had an increased number of osteoclasts on bone surfaces and an overall decreased bone density. The researchers believe that S1P signals osteoclast precursors to leave the bone and move into the blood before they fully mature. Supporting this idea, they found that activating the S1P receptor in a postmenopausal osteoporosis mouse model caused an increased number of immature osteoclasts in the blood and an increase in bone density.

“Most current therapies for bone-degrading diseases target mature osteoclasts,” says NIAID Director Dr. Anthony S. Fauci. Controlling the migration of osteoclast precursors to restore the balance of bone homeostasis is a potential new approach to treating and preventing joint and bone diseases.

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