Bad for the Bones: Thwarted hormone leads to skeletal decay

A hormone with one widely recognized task may not be single purposed after all. Thyroid-stimulating hormone (TSH), which is made in the pituitary gland and circulates in the body, pumps up production of thyroid hormone, an important regulator of metabolism. Now, research demonstrates that TSH also affects the constant remodeling of bone: Lab mice that aren’t responsive to TSH show signs of the bone-thinning disease osteoporosis.

Mone Zaidi of Mount Sinai School of Medicine in New York and his colleagues created mice missing half or all copies of the TSH receptor, the cell membrane protein to which the hormone must bind to initiate any of its actions. The mice devoid of TSH receptors were small and sickly and died within 10 weeks.

Mice with half the usual number of TSH receptors appeared healthy but had a hidden problem. Although they made normal amounts of thyroid hormone, these mice had frail bones that were rapidly remodeling themselves–simultaneously destroying existing bone while adding new tissue inappropriately. Thyroid hormone deficiencies weren’t responsible for the defect, Zaidi says, because even when these mice were given additional thyroid hormone, they still showed bone defects.

“As a physician and as a scientist, I learned that the only function of TSH is to regulate thyroid hormone production,” says Zaidi, whose findings appear in the Oct. 17 Cell. In this experiment, however, animals with depleted TSH receptors had normal thyroid function but brittle bones. “It really contradicts the textbook picture,” he says.

In healthy skeletons, two cell types work in concert to constantly remodel bone. Osteoclasts break down bone structures, while osteoblasts form new bone. Zaidi and his colleagues found that a lack of TSH receptors leads to overactive and unusually long-lived osteoclasts and osteoblasts.

Conversely, when the scientists added TSH to cultures of normal osteoclasts and osteoblasts, their activity diminished. TSH and its receptor appeared to act through separate chemical pathways in each of the two cell types, and the effect was greater in the bone-destroying cells. Altering the amounts of TSH or its receptor can thus disrupt the delicate balance of bone remodeling, says Zaidi.

Physicians had long observed a relationship between an overactive thyroid gland and osteoporosis but generally attributed the bone disease to the increase in thyroid hormone. While there have been studies suggesting that elevated thyroid does affect some aspects of bone physiology, Zaidi’s results suggest another explanation: The drop in TSH concentrations that results from excess thyroid hormone could cause the observed bone loss.

Because bone weakening appeared in mice that still had half their TSH receptors intact, “normal variations [of TSH] that you might see in a human population might be contributing to bone mass,” says Deborah V. Novack of Washington University School of Medicine in St. Louis.

Both Novack and Zaidi see promise in the TSH molecule and its receptor for designing diagnostic tools and therapies for osteoporosis, a disease that Zaidi calls “perhaps one of the most underdiagnosed and undertreated public health problems.”

Treatment based on TSH might not be simple, however, since osteoporosis can remain hidden for decades, says John R. Klein of the University of Texas Health Science Center in Houston. Still, the study “brings a new dimension into the way we think about how bone remodeling occurs,” says Klein. “TSH, a molecule that few people would have ever imagined was involved in regulating bone remodeling, is in fact a major player in the process.”

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