title: Genetic confirmation for a central role for TNFα in the direct action of thyroid stimulating hormone on the skeleton.
abstract: Clinical data showing correlations between low thyroid-stimulating hormone (TSH) levels and high bone turnover markers, low bone mineral density, and an increased risk of osteoporosis-related fractures are buttressed by mouse genetic and pharmacological studies identifying a direct action of TSH on the skeleton. Here we show that the skeletal actions of TSH deficiency are mediated, in part, through TNFα. Compound mouse mutants generated by genetically deleting the Tnfα gene on a Tshr(-/-) (homozygote) or Tshr(+/-) (heterozygote) background resulted in full rescue of the osteoporosis, low bone formation, and hyperresorption that accompany TSH deficiency. Studies using ex vivo bone marrow cell cultures showed that TSH inhibits and stimulates TNFα production from macrophages and osteoblasts, respectively. TNFα, in turn, stimulates osteoclastogenesis but also enhances the production in bone marrow of a variant TSHβ. This locally produced TSH suppresses osteoclast formation in a negative feedback loop. We speculate that TNFα elevations due to low TSH signaling in human hyperthyroidism contribute to the bone loss that has traditionally been attributed solely to high thyroid hormone levels.
authors.affiliation: The Mount Sinai Bone Program and Department of Medicine and Pediatrics, Mount Sinai School of Medicine, New York, NY 10029, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Sun
authors.forename: Ling-Ling
authors.initials: LL
authors.lastname: Zhu
authors.forename: Ping
authors.initials: P
authors.lastname: Lu
authors.forename: Tony
authors.initials: T
authors.lastname: Yuen
authors.forename: Jianhua
authors.initials: J
authors.lastname: Li
authors.forename: Risheng
authors.initials: R
authors.lastname: Ma
authors.forename: Ramkumarie
authors.initials: R
authors.lastname: Baliram
authors.forename: Ramkumari
authors.initials: R
authors.lastname: Baliram
authors.forename: Surinder S
authors.initials: SS
authors.lastname: Moonga
authors.forename: Peng
authors.initials: P
authors.lastname: Liu
authors.forename: Alberta
authors.initials: A
authors.lastname: Zallone
authors.forename: Maria I
authors.initials: MI
authors.lastname: New
authors.forename: Terry F
authors.initials: TF
authors.lastname: Davies
authors.forename: Mone
authors.initials: M
authors.lastname: Zaidi
mesh_terms: D000818:Animals; D015519:Bone Density; D001862:Bone Resorption / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D006801:Humans; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism; D010012:Osteogenesis; D010024:Osteoporosis / Q000235:genetics / Q000378:metabolism; D011989:Receptors, Thyrotropin / Q000235:genetics / Q000378:metabolism*; D013972:Thyrotropin / Q000378:metabolism* / Q000494:pharmacology; D037322:Thyrotropin, beta Subunit / Q000378:metabolism / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*
chemical_list: D011989:Receptors, Thyrotropin; D037322:Thyrotropin, beta Subunit; D014409:Tumor Necrosis Factor-alpha; D013972:Thyrotropin
keywords: bone density; bone metabolism; thyroid disease