Intermittent recombinant TSH injections prevent ovariectomy-induced bone loss.
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.
Sun
Li
L
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, USA.
Vukicevic
Slobodan
S
Baliram
Ramkumarie
R
Yang
Guozhe
G
Sendak
Rebecca
R
McPherson
John
J
Zhu
Ling-Ling
LL
Iqbal
Jameel
J
Latif
Rauf
R
Natrajan
Arjun
A
Arabi
Ario
A
Yamoah
Kosj
K
Moonga
Baljit S
BS
Gabet
Yankel
Y
Davies
Terry F
TF
Bab
Itai
I
Abe
Etsuko
E
Sampath
Kuber
K
Zaidi
Mone
M
D000818:Animals; D015519:Bone Density; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D007267:Injections; D051379:Mice; D010010:Osteoclasts / Q000378:metabolism; D010024:Osteoporosis / Q000378:metabolism / Q000517:prevention & control*; D010052:Ovariectomy; D051381:Rats; D011989:Receptors, Thyrotropin / Q000378:metabolism; D011994:Recombinant Proteins / Q000008:administration & dosage; D013314:Stress, Mechanical; D013972:Thyrotropin / Q000008:administration & dosage*; D013974:Thyroxine / Q000097:blood
D011989:Receptors, Thyrotropin; D011994:Recombinant Proteins; D013972:Thyrotropin; D013974:Thyroxine