Thyroid-stimulating hormone restores bone volume, microarchitecture, and strength in aged ovariectomized rats.
We show the systemic administration of low levels of TSH increases bone volume and improves bone microarchitecture and strength in aged OVX rats. TSH's actions are mediated by its inhibitory effects on RANKL-induced osteoclast formation and bone resorption coupled with stimulatory effects on osteoblast differentiation and bone formation, suggesting TSH directly affects bone remodeling in vivo.


BACKGROUND
Thyroid-stimulating hormone (TSH) receptor haploinsufficient mice with normal circulating thyroid hormone levels have reduced bone mass, suggesting that TSH directly affects bone remodeling. We examined whether systemic TSH administration restored bone volume in aged ovariectomized (OVX) rats and influenced osteoclast formation and osteoblast differentiation in vitro.


METHODS
Sprague-Dawley rats were OVX at 6 months, and TSH therapy was started immediately after surgery (prevention mode; n = 80) or 7 mo later (restoration mode; n = 152). Hind limbs and lumbar spine BMD was measured at 2- or 4-wk intervals in vivo and ex vivo on termination at 8-16 wk. Long bones were subjected to microCT, histomorphometric, and biomechanical analyses. The direct effect of TSH was examined in osteoclast and osteoblast progenitor cultures and established rat osteosarcoma-derived osteoblastic cells. Data were analyzed by ANOVA Dunnett test.


RESULTS
In the prevention mode, low doses (0.1 and 0.3 microg) of native rat TSH prevented the progressive bone loss, and importantly, did not increase serum triiodothyroxine (T3) and thyroxine (T4) levels in aged OVX rats. In restoration mode, animals receiving 0.1 and 0.3 microg TSH had increased BMD (10-11%), trabecular bone volume (100-130%), trabecular number (25-40%), trabecular thickness (45-60%), cortical thickness (5-16%), mineral apposition and bone formation rate (200-300%), and enhanced mechanical strength of the femur (51-60%) compared with control OVX rats. In vitro studies suggest that TSH's action is mediated by its inhibitory effects on RANKL-induced osteoclast formation, as shown in hematopoietic stem cells cultivated from TSH-treated OVX rats. TSH also stimulates osteoblast differentiation, as shown by effects on alkaline phosphatase activity, osteocalcin expression, and mineralization rate.


CONCLUSIONS
These results show for the first time that systemically administered TSH prevents bone loss and restores bone mass in aged OVX rats through both antiresorptive and anabolic effects on bone remodeling.
Sampath
T Kuber
TK
Genzyme Corporation, Framingham, Massachusetts 01701-9322, USA. kuber.sampath@genzyme.com
Simic
Petra
P
Sendak
Rebecca
R
Draca
Natasa
N
Bowe
Ann E
AE
O'Brien
Stephen
S
Schiavi
Susan C
SC
McPherson
John M
JM
Vukicevic
Slobodan
S
D000469:Alkaline Phosphatase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001696:Biomechanical Phenomena; D015519:Bone Density / Q000187:drug effects; D001842:Bone and Bones / Q000033:anatomy & histology / Q000737:chemistry / Q000187:drug effects*; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D005260:Female; D005269:Femur / Q000033:anatomy & histology / Q000737:chemistry / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006614:Hindlimb / Q000737:chemistry / Q000187:drug effects; D008159:Lumbar Vertebrae / Q000737:chemistry / Q000187:drug effects / Q000502:physiology; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015675:Osteocalcin / Q000235:genetics; D010010:Osteoclasts / Q000737:chemistry / Q000166:cytology / Q000187:drug effects; D010024:Osteoporosis / Q000503:physiopathology / Q000517:prevention & control; D010052:Ovariectomy; D051381:Rats; D017207:Rats, Sprague-Dawley; D013972:Thyrotropin / Q000494:pharmacology* / Q000627:therapeutic use; D013974:Thyroxine / Q000097:blood; D013977:Tibia / Q000737:chemistry / Q000187:drug effects / Q000502:physiology; D014284:Triiodothyronine / Q000097:blood
D014284:Triiodothyronine; D015675:Osteocalcin; D013972:Thyrotropin; D000469:Alkaline Phosphatase; D013974:Thyroxine