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Published online on March 10, 2008, 10.1073/pnas.0712395105
PNAS | March 18, 2008 | vol. 105 | no. 11 | 4289-4294


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BIOLOGICAL SCIENCES / MEDICAL SCIENCES
Intermittent recombinant TSH injections prevent ovariectomy-induced bone loss

Li Sun*, Slobodan Vukicevic{dagger}, Ramkumarie Baliram*, Guozhe Yang*, Rebecca Sendak{ddagger}, John McPherson{dagger}, Ling-Ling Zhu*, Jameel Iqbal*, Rauf Latif*, Arjun Natrajan*, Ario Arabi*, Kosj Yamoah*, Baljit S. Moonga*, Yankel Gabet§, Terry F. Davies*, Itai Bab§, Etsuko Abe*, Kuber Sampath{ddagger}, and Mone Zaidi*,¶

*The Mount Sinai Bone Program and The Thyroid Research Unit at the Bronx Veterans Affairs Medical Center, Mount Sinai School of Medicine, New York, NY 10029; {dagger}Laboratory of Mineralized Tissues, 10000 Zagreb, Croatia; {ddagger}Genzyme Corporation, Framingham, MA 02142; and §Bone Laboratory, The Hebrew University of Jerusalem, Jerusalem 91904, Israel

Communicated by Maria Iandolo New, Mount Sinai School of Medicine, New York, NY, January 2, 2008 (received for review November 24, 2007)

We recently described the direct effects of thyroid-stimulating hormone (TSH) on bone and suggested that the bone loss in hyperthyroidism, hitherto attributed solely to elevated thyroid hormone levels, could at least in part arise from accompanying decrements in serum TSH. Recent studies on both mice and human subjects provide compelling evidence that thyroid hormones and TSH have the opposite effects on the skeleton. Here, we show that TSH, when injected intermittently into rodents, even at intervals of 2 weeks, displays a powerful antiresorptive action in vivo. By virtue of this action, together with the possible anabolic effects shown earlier, TSH both prevents bone loss and restores the lost bone after ovariectomy. Importantly, the osteoclast inhibitory action of TSH persists ex vivo even after therapy is stopped for 4 weeks. This profound and lasting antiresorptive action of TSH is mimicked in cells that genetically overexpress the constitutively active ligand-independent TSH receptor (TSHR). In contrast, loss of function of a mutant TSHR (Pro -> Leu at 556) in congenital hypothyroid mice activates osteoclast differentiation, confirming once again our premise that TSHRs have a critical role in regulating bone remodeling.

osteoclast | osteoporosis | pituitary | osteoblast | bisphosphonate

Author contributions: L.S., S.V., G.Y., J.M., J.I., T.F.D., I.B., E.A., K.S., and M.Z. designed research; L.S., S.V., R.B., G.Y., L.-L.Z., J.I., R.L., A.N., A.A., K.Y., Y.G., and E.A. performed research; R.S. and J.M. contributed new reagents/analytic tools; L.S., S.V., G.Y., B.S.M., T.F.D., I.B., E.A., K.S., and M.Z. analyzed data; and L.S., J.I., B.S.M., and M.Z. wrote the paper.

Conflict of interest statement: R.S., J.M., and K.S. are employees of Genzyme Corporation.

To whom correspondence should be addressed. E-mail: mone.zaidi{at}mountsinai.org

© 2008 by The National Academy of Sciences of the USA


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