Thyroid hormone excess rather than thyrotropin deficiency induces osteoporosis in hyperthyroidism.
Thyrotoxicosis is an important but under recognized cause of osteoporosis. Recently, TSH deficiency, rather than thyroid hormone excess, has been suggested as the underlying cause. To investigate the molecular mechanism of osteoporosis in thyroid disease, we characterized the skeleton in mice lacking either thyroid hormone receptor alpha or beta (TRalpha(0/0), TRbeta-/-). Remarkably, in the presence of normal circulating thyroid hormone and TSH concentrations, adult TRalpha(0/0) mice had osteosclerosis accompanied by reduced osteoclastic bone resorption, whereas juveniles had delayed endochondral ossification with reduced bone mineral deposition. By contrast, adult TRbeta-/- mice with elevated TSH and thyroid hormone levels were osteoporotic with evidence of increased bone resorption, whereas juveniles had advanced ossification with increased bone mineral deposition. Analysis of T3 target gene expression revealed skeletal hypothyroidism in TRalpha(0/0) mice, but skeletal thyrotoxicosis in TRbeta-/- mice. These studies demonstrate that bone loss in thyrotoxicosis is independent of circulating TSH levels and mediated predominantly by TRalpha, thus identifying TRalpha as a novel drug target in the prevention and treatment of osteoporosis.
Bassett
J H Duncan
JH
Molecular Endocrinology Group, Division of Medicine and Medical Research Council (MRC) Clinical Sciences Centre, Imperial College London, Hammersmith Hospital, London W12 0NN, United Kingdom.
O'Shea
Patrick J
PJ
Sriskantharajah
Srividya
S
Rabier
Bénédicte
B
Boyde
Alan
A
Howell
Peter G T
PG
Weiss
Roy E
RE
Roux
Jean-Paul
JP
Malaval
Luc
L
Clement-Lacroix
Phillipe
P
Samarut
Jacques
J
Chassande
Olivier
O
Williams
Graham R
GR
D000375:Aging; D000818:Animals; D000831:Animals, Newborn; D015519:Bone Density; D001862:Bone Resorption / Q000235:genetics; D001842:Bone and Bones / Q000473:pathology / Q000648:ultrastructure; D004622:Embryo, Mammalian; D006980:Hyperthyroidism / Q000473:pathology / Q000503:physiopathology*; D051379:Mice; D018345:Mice, Knockout; D008855:Microscopy, Electron, Scanning; D010024:Osteoporosis / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D037021:Thyroid Hormone Receptors alpha / Q000172:deficiency / Q000235:genetics; D037042:Thyroid Hormone Receptors beta / Q000172:deficiency / Q000235:genetics; D013963:Thyroid Hormones / Q000502:physiology*; D013972:Thyrotropin / Q000172:deficiency* / Q000502:physiology
D037021:Thyroid Hormone Receptors alpha; D037042:Thyroid Hormone Receptors beta; D013963:Thyroid Hormones; D013972:Thyrotropin