title: Thyroid hormone receptor-β1 signaling is critically involved in regulating secondary ossification via promoting transcription of the Ihh gene in the epiphysis.
abstract: Thyroid hormone (TH) action is mediated through two nuclear TH receptors, THRα and THRβ. Although the role of THRα is well established in bone, less is known about the relevance of THRβ-mediated signaling in bone development. On ther basis of our recent finding that TH signaling is essential for initiation and formation of secondary ossification center, we evaluated the role of THRs in mediating TH effects on epiphysial bone formation. Two-day treatment of TH-deficient Tshr(-/-) mice with TH increased THRβ1 mRNA level 3.4-fold at day 7 but had no effect on THRα1 mRNA level at the proximal tibia epiphysis. Treatment of serum-free cultures of tibias from 3-day-old mice with T3 increased THRβ1 expression 2.1- and 13-fold, respectively, at 24 and 72 h. Ten-day treatment of Tshr(-/-) newborns (days 5-14) with THRβ1 agonist GC1 at 0.2 or 2.0 μg/day increased BV/TV at day 21 by 225 and 263%, respectively, compared with vehicle treatment. Two-day treatment with GC1 (0.2 μg/day) increased expression levels of Indian hedgehog (Ihh) 100-fold, osterix 15-fold, and osteocalcin 59-fold compared with vehicle at day 7 in the proximal tibia epiphysis. Gel mobility shift assay demonstrated that a putative TH response element in the distal promoter of mouse Ihh gene interacted with THRβ1. GC1 treatment (1 nM) increased Ihh distal promoter activity 20-fold after 48 h in chondroctyes. Our data suggest a novel role for THRβ1 in secondary ossification at the epiphysis that involves transcriptional upregulation of Ihh gene.
authors.affiliation: Musculoskeletal Disease Center, Veterans Affairs Loma Linda Healthcare System, Loma Linda, California; Department of Medicine, Loma Linda University, Loma Linda, California;
authors.forename: Weirong
authors.initials: W
authors.lastname: Xing
authors.affiliation: Musculoskeletal Disease Center, Veterans Affairs Loma Linda Healthcare System, Loma Linda, California;
authors.forename: Patrick
authors.initials: P
authors.lastname: Aghajanian
authors.affiliation: Musculoskeletal Disease Center, Veterans Affairs Loma Linda Healthcare System, Loma Linda, California;
authors.forename: Helen
authors.initials: H
authors.lastname: Goodluck
authors.affiliation: Musculoskeletal Disease Center, Veterans Affairs Loma Linda Healthcare System, Loma Linda, California; Department of Medicine, Loma Linda University, Loma Linda, California;
authors.forename: Chandrasekhar
authors.initials: C
authors.lastname: Kesavan
authors.affiliation: Musculoskeletal Disease Center, Veterans Affairs Loma Linda Healthcare System, Loma Linda, California;
authors.forename: Shaohong
authors.initials: S
authors.lastname: Cheng
authors.affiliation: Musculoskeletal Disease Center, Veterans Affairs Loma Linda Healthcare System, Loma Linda, California;
authors.forename: Sheila
authors.initials: S
authors.lastname: Pourteymoor
authors.affiliation: Musculoskeletal Disease Center, Veterans Affairs Loma Linda Healthcare System, Loma Linda, California;
authors.forename: Heather
authors.initials: H
authors.lastname: Watt
authors.affiliation: Musculoskeletal Disease Center, Veterans Affairs Loma Linda Healthcare System, Loma Linda, California;
authors.forename: Catrina
authors.initials: C
authors.lastname: Alarcon
authors.affiliation: Musculoskeletal Disease Center, Veterans Affairs Loma Linda Healthcare System, Loma Linda, California; Department of Medicine, Loma Linda University, Loma Linda, California; Department of Orthopedics, Loma Linda University, Loma Linda, California; and Department of Biochemistry, Loma Linda University, Loma Linda, California Subburaman.Mohan@va.gov.
authors.forename: Subburaman
authors.initials: S
authors.lastname: Mohan
mesh_terms: D000818:Animals; D001846:Bone Development / Q000235:genetics; D004838:Epiphyses / Q000378:metabolism*; D005260:Female; D018507:Gene Expression Regulation, Developmental; D053823:Hedgehog Proteins / Q000187:drug effects / Q000235:genetics*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010012:Osteogenesis / Q000235:genetics*; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D011989:Receptors, Thyrotropin / Q000235:genetics; D015398:Signal Transduction; D037021:Thyroid Hormone Receptors alpha / Q000235:genetics; D037042:Thyroid Hormone Receptors beta / Q000819:agonists / Q000235:genetics*; D013974:Thyroxine / Q000494:pharmacology; D013977:Tibia / Q000378:metabolism*; D014284:Triiodothyronine / Q000494:pharmacology; D015854:Up-Regulation
chemical_list: D053823:Hedgehog Proteins; D012333:RNA, Messenger; D011989:Receptors, Thyrotropin; D037021:Thyroid Hormone Receptors alpha; D037042:Thyroid Hormone Receptors beta; C514061:ihh protein, mouse; D014284:Triiodothyronine; D013974:Thyroxine
keywords: Indian hedge hog; bone formation; chondrocytes; hypothyroidism; ossification; osteoblasts; thyroid hormones