Sci. Aging Knowl. Environ., 22 October 2003
Vol. 2003, Issue 42, p. nw143
[DOI: 10.1126/sageke.2003.42.nw143]


Bone Surprise

Hormone reveals unexpected skeleton-bolstering power

R. John Davenport;2003/42/nw143

Key Words: NF{kappa}B • LRP5 • JNK • VEGF • Flk • osteosclerosis

A hormone renowned for goading the thyroid gland now reveals a talent for restraining bone destruction, according to new work. The study uncovers an unexpected reason why an overactive thyroid triggers osteoporosis, and it could lead researchers to novel bone-boosting drugs.

To keep the skeleton healthy, cells called osteoclasts break down old bone and cells known as osteoblasts replace it (see "The Plot Thickens on Thin Bones"). When osteoclasts outpace osteoblasts, osteoporosis results. This skeleton-weakening disease occurs in women because of estrogen loss after menopause and in both genders because of other age-related factors. Hoping to discover ways to maintain bone strength, researchers are striving to understand the balance between the two cells' activities, and they're gaining clues. For instance, osteoporosis occurs in people with hyperactive thyroid glands. Researchers conjectured that too much thyroid hormone spurs bone loss. Another hormone--released by the pituitary gland--called thyroid-stimulating hormone (TSH) prods the thyroid to release thyroid hormone. People with overactive thyroids exhibit low TSH concentrations because thyroid hormone loops back to the pituitary gland and shuts down TSH production. Low TSH, rather than excess thyroid hormone, might weaken bone, posited osteoporosis researcher Mone Zaidi of Mount Sinai School of Medicine in New York City.

To address that question, Zaidi and colleagues studied mice that lack the gene for the TSH receptor protein; without this protein, cells can't respond to TSH. Animals with no receptor genes displayed shriveled thyroids and thin bones. Animals with one good copy also had thin bones, but their blood contained normal amounts of thyroid hormone. That result suggests that the absence of TSH--not an abundance of thyroid hormone--undermines bones.

Further analysis revealed that mice lacking one or two copies of the gene had overactive osteoclasts and osteoblasts. The findings suggest that TSH normally restrains both types of cells. Additional experiments support that notion. In culture, TSH hampered the maturation and activity of osteoclasts and osteoblasts. The team also identified signaling molecules squelched by TSH that normally rouse the bone-breakers and -builders; in osteoclasts, TSH dampened the production of proteins prodded by RANKL, a crucial activator of the bone-dissolving cells (see "RAINing on the RANK Parade"). Although the absence of TSH seems to stimulate both types of bone cells, osteoclasts apparently respond more strongly, because the animals suffer bone loss. Zaidi says that activating the TSH receptor with drugs might help stall osteoporosis in postmenopausal women, which results from hyperactive osteoclasts. He adds that such drugs might not work in age-related osteoporosis, in which osteoblasts falter.

"No one ever really thought that it would be TSH and not thyroid hormone," says pathologist Deborah Novack of Washington University School of Medicine in St. Louis, Missouri. Researchers should investigate whether people with naturally small amounts of TSH are especially prone to osteoporosis, she adds. Bone biologist Patrick Ross, also at Washington University, notes that pathways other than those activated by RANKL also spur osteoclasts, and he would like to know whether TSH quiets those circuits too. Such experiments should help researchers better understand TSH's newfound skill for strengthening bone.

--R. John Davenport

October 22, 2003
  1. E. Abe et al., TSH is a negative regulator of skeletal remodeling. Cell 115, 151-162 (2003). [Abstract] [Full Text] [CrossRef][Medline]
Citation: R. J. Davenport, Bone Surprise. Sci. SAGE KE 2003 (42), nw143 (2003).

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