Protein may be cause of osteoporosis

Agnes Vignery, a professor of orthopedics at the School of Medicine, grew up avoiding prepared food, eating fresh vegetables and climbing the 15 flights of stairs to her Paris apartment every day.

She partially credits the typical American alternative to that lifestyle — “eating a lot of pills and junk food and using a car to go around the corner” — with the rise in osteoporosis, a decline in bone density and quality that affects more than half of Americans over 50.

But there’s more to it than a couch-potato lifestyle: Vignery’s research group, consisting of researchers at the School of Medicine, the University of Pennsylvania and Pfizer, recently identified a possible molecular cause of the disease.

The team found a regulatory molecule, called IRAK-M, that affects the activity of osteoclasts, the cells that chew through bone mass during natural bone reformation. Over the course of a decade, the human body naturally replaces all bone matter, Vignery said.

The study, published in the latest issue of the Journal of Experimental Medicine, showed that IRAK-M acts as a biochemical speed bump for osteoclasts. Since it is structurally an enzyme known as a kinase, Vignery said fewer other kinases are put to work when IRAK-M is present, even though it does not contribute to bone degradation the way its structural twins do.

She said the equilibrium between positive and negative regulators of osteoclasts which IRAK-M helps maintain is vital.

“You have to have a yin and a yang, a balance between powers,” Vignery said.

If genetic mutations affect the expression or activity of IRAK-M, this balance is thrown off, and osteoclasts outperform their bone-mass-producing counterparts, the osteoblasts, leading to a predisposition for osteoporosis, she said.

Felicia Cosman, clinical director of the National Osteoporosis Foundation, said researchers agree that 70 percent of a patient’s bone-mass level is determined by genetics — osteoclasts are influenced by a variety of hormonal and mechanical factors.

However, the remaining 30 percent of the bone-mass level can be maximized by a calcium-rich diet, weight-bearing exercises and the presence of estrogen, according to Christine Gerbstadt, a national spokesperson for the American Dietetic Association.

By the time the first warning signs of osteoporosis, such as an increased tendency for fracture, have surfaced, an individual already has the disease.

“It is a silent disease,” Vignery said. “You lose your bone, and you don’t know it is happening until your spine crushes and you are in a wheelchair.”

Close to half of women who break a hip, a common side effect of osteoporosis, when they are over 60 years of age die within two years, Gerbstadt said.

“They need surgery and get a blood clot in their lung or a urinary-tract infection or are so debilitated and protein-malnourished that they can’t fight off the next flu outbreak,” she said. “Women in their 20s and 30s always assume that there will be a cure by the time they are older. The scary part is that I read that statistic a decade ago, and it has not changed.”

Vignery said she plans to look for mutated versions of IRAK-M in patients with osteoporosis and at the hormones and receptors affecting IRAK-M’s expression.

Linda Pellico, a professor at the School of Nursing, shows students at Seth Haley School in West Haven a lung. As part of ‘Have Bones, Will Travel,’ she presents organs at local schools.
Courtesy LindaPellico
Linda Pellico, a professor at the School of Nursing, shows students at Seth Haley School in West Haven a lung. As part of ‘Have Bones, Will Travel,’ she presents organs at local schools.

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