title: Thyroid-stimulating hormone induces a Wnt-dependent, feed-forward loop for osteoblastogenesis in embryonic stem cell cultures.
abstract: We have shown that the anterior pituitary hormone, thyroid-stimulating hormone (TSH), can bypass the thyroid to exert a direct protective effect on the skeleton. Thus, we have suggested that a low TSH level may contribute to the bone loss of hyperthyroidism that has been attributed traditionally to high thyroid hormone levels. Earlier mouse genetic, cell-based, and clinical studies together have established that TSH inhibits osteoclastic bone resorption. However, the direct influence of TSH on the osteoblast has remained unclear. Here, we have used a model system developed from murine ES cells, induced to form mature mineralizing osteoblasts, and show that TSH stimulates osteoblast differentiation primarily through the activation of protein kinase Cδ and the up-regulation of the noncanonical Wnt components frizzled and Wnt5a. We predict that a TSH-induced, fast-forward short loop in bone marrow permits Wnt5a production, which, in addition to enhancing osteoblast differentiation, also stimulates osteoprotegerin secretion to attenuate bone resorption by neighboring osteoclasts. We surmise that this loop should uncouple bone formation from bone resorption with a net increase in bone mass, which is what has been observed upon injecting TSH.
authors.affiliation: Thyroid Research Laboratory, Mount Sinai School of Medicine, and James J Peters VA Medical Center, New York, NY 10029, USA.
authors.forename: Ramkumarie
authors.initials: R
authors.lastname: Baliram
authors.forename: Rauf
authors.initials: R
authors.lastname: Latif
authors.forename: Joshua
authors.initials: J
authors.lastname: Berkowitz
authors.forename: Simon
authors.initials: S
authors.lastname: Frid
authors.forename: Graziana
authors.initials: G
authors.lastname: Colaianni
authors.forename: Li
authors.initials: L
authors.lastname: Sun
authors.forename: Mone
authors.initials: M
authors.lastname: Zaidi
authors.forename: Terry F
authors.initials: TF
authors.lastname: Davies
mesh_terms: D000818:Animals; D001846:Bone Development; D053595:Embryonic Stem Cells / Q000166:cytology*; D051379:Mice; D010006:Osteoblasts / Q000166:cytology*; D013972:Thyrotropin / Q000502:physiology*; D051153:Wnt Proteins / Q000502:physiology*
chemical_list: D051153:Wnt Proteins; D013972:Thyrotropin