Table 1.

Skeletal Phenotype of Genetically Modified Mice

Mouse Model	Genotype	Systemic Thyroid Status	Developing Skeleton	Adult Skeleton	T3 Action in Bone	Refs.
Congenital hypothyroid
Pax8−/−	Maximal Tshr signaling Apo TRα and TRβ	No Thyroid T4 undetectable T3 undetectable TSH 1900×	Impaired linear growth, delayed endochondral ossification, reduced cortical bone, reduced bone mineralization	Majority die by weaning; coarse plate-like trabeculae with impaired trabecular remodeling; reduced cortical thickness; reduced mineralization	Reduced T3 action	138, 282, 314
TSHR mutants
Tshr−/−	No Tshr Apo TRα and TRβ	Thyroid hypoplasia T4 undetectable T3 undetectable TSH > 500×	Severe growth retardation; impaired linear growth; reduced mineral density; increased bone resorption; increased bone formation or decreased bone formation	Die by weaning unless treated with thyroid extract Low bone mass, high bone turnover not reversed by thyroid extract supplementation Enhanced bone loss in supplemented animals rendered thyrotoxic	NR	32, 140, 153, 276
TshrP556L/P556L(hyt/hyt)	Absent Tshr signaling	Thyroid hypoplasia	Impaired linear growth, delayed endochondral ossification, reduced cortical bone, reduced bone mineralization	NR	Reduced T3 action	138, 529
	Apo TRα and TRβ	T4 0.06×
		T3 0.06×
		TSH 2300×
Gpb5−/−	No thyrostimulin (Alternative high affinity Tshr ligand)	Juveniles: T4 0.7×, (males only)	Normal linear growth; endochondral and intramembranous ossification; increased bone volume and mineralization due to increased osteoblastic bone formation	Skeletal phenotype resolved by early adulthood	NR	139
		T3 normal
		TSH 3 × (males only)
		Adults: T4,T3 and TSH normal
Compound mutants
Tshr−/−Tnfα−/−	No Tshr or TNFα	Treated with thyroid extract from weaning: T4, T3, and TSH not reported	NR	Amelioration of low bone mass, high bone turnover phenotype in Tshr−/− mice	NR	153
TR mutants
TRα mutants
TRα−/−	No TRα1 or TRα2; TRΔα1 and TRΔα2 preserved	Hypothyroid: T4 0.1× T3 0.4× TSH 2× (GH normal)	Severe growth delay; delayed endochondral ossification; impaired chondrocyte differentiation; reduced mineralization	Die by weaning unless T3 treated	NR	73, 310, 311
TRα1−/−	No TRα1 or TRΔα1; TRα2 and TRΔα2 preserved	Mild hypothyroidism T4 0.7 × (males only) T3 normal TSH 0.8×	No growth retardation	NR	NR	304
TRα2−/−	No TRα2 or TRΔα2	Mild hypothyroidism	No growth retardation	Reduced BMD; reduced cortical bone	NR	253
	TRα1 and TRΔα1 over-expression	T4 0.8×	Normal endochondral ossification
		T3 0.7×
		TSH normal
		(GH normal, IGF-1 low)
TRα1GFP/GFP	No TRα2 2× increase in TRα1GFP	Euthyroid, T4, T3 and TSH normal	Normal postnatal growth	NR	NR	308
TRα0/0	No TRα	Euthyroid	Transient growth delay, delayed endochondral ossification, impaired chondrocyte differentiation, reduced mineral deposition	Osteosclerosis, increased trabecular bone volume, reduced osteoclastic bone resorption	Reduced T3 action	285, 313
	Normal TRβ	T4 normal
		T3 normal
		TSH normal
		(GH normal)
TRα1PV/+	Heterozygous dominant-negative TRα receptor	Euthyroid T4 normal T3 1.2× TSH 1.5–2× (GH normal)	Severe persistent growth retardation; delayed intramembranous and endochondral ossification; impaired chondrocyte differentiation; reduced mineralization	Grossly dysmorphic bones; impaired ossification and bone modelling; Osteosclerosis, increased trabecular and cortical bone volume; reduced osteoclastic bone resorption (resistant to T4 treatment)	Reduced T3 action	278, 317, 319
TRα1R384C/+	Heterozygous dominant-negative TRα receptor (10 × lower affinity for T3)	Euthyroid adults Mild hypothyroidism (P10–35) T4 0.8× T3 0.7× TSH 0.7× (GH reduced in juveniles)	Transient growth delay; delayed intramembranous and endochondral ossification; impaired chondrocyte differentiation	Impaired bone modelling; osteosclerosis, increased trabecular bone volume; increased mineralization; reduced osteoclastic bone resorption (ameliorated by T3 treatment)	Reduced T3 action	312, 530
TRα1R398H/+	Heterozygous dominant-negative TRα receptor	Euthyroid juvenilesT4 and T3 normal TSH 3.4×	NR	NR	NR	531
TRα1L400R/+ (TRAMI/+xSycp1-Cre)	Global expression dominant-negative receptor TRα1L400R	Euthyroid T4 and T3 normal TSH normal (GH low)	Severe persistent growth retardation; delayed endochondral ossification	NR	NR	320
TRα1L400R/+/C1 (TRAMI/+x Col1a1-Cre)	Osteoblast expression dominant-negative receptor TRα1L400R	Euthyroid, T4 and T3 and TSH normal	No skeletal abnormalities reported after limited analysis	No skeletal abnormalities reported after limited analysis	NR	321
TRα1L400R/+/C2 (TRAMI/+x Col2a1-Cre)	Chondrocyte and osteoblast expression dominant-negative receptor TRα1L400R	Euthyroid, T4 and T3 and TSH normal	Persistent growth retardation Delay in endochondral ossification Skull abnormalities Reduced cortical and trabecular bone Decreased mineralization	Short stature	NR	321
TRβ mutants
TRβ−/−	No TRβ Normal TRα	RTH and goiter T4 3–4× T3 3–4× TSH 2.6–8×	Persistent short stature, advanced endochondral and intramembranous ossification, increased mineral deposition	Osteoporosis, reduced mineralization, increased osteoclastic bone resorption	Increased T3 action	9, 80, 285, 312, 313
TRβ2−/−	No TRβ2 TRβ1 preserved	Mild RTH T4 1–3× T3 1.3–1.5× TSH 1.2–2.5×	No growth abnormality	NR	NR	78, 309
TRβPV/PV	Homozygous dominant-negative TRβ receptor	Severe RTH and goiter T4 15× T3 9× TSH 400×	Accelerated prenatal growth; persistent postnatal growth retardation; advanced intramembranous and endochondral ossification; increased mineralization	NR	Increased T3 action	164, 278, 323
TRβΔ337T/Δ337T	Homozygous dominant-negative TRβ receptor	Severe RTH and goiter T4 15× T3 10× TSH 50×	No growth phenotype	NR	NR	82
TRβ transgenics
TshbTRβG345R	Pituitary expression of dominant-negative TRβG345R	RTH T4 1.2× TSH normal	Normal growth	NR	NR	532
CgaTRβΔ337T	Pituitary expression of dominant-negative TRβΔ337T	T4 normal TSH 3× (Reduced bioavailability?)	NR	NR	NR	533
ActbTRβPV	Ubiquitous expression of dominant-negative TRβPV	RTH T4 1.5× TSH normal	Impaired weight gain	NR	NR	534
CgaTRβPV	Pituitary expression of dominant-negative TRβPV	Euthyroid T4, T3 and TSH normal	Impaired weight gain	NR	NR	535
Compound mutants
TRα−/−TRβ−/−	No TRα1, TRα2 or TRβ TRΔα1 and TRΔα2 preserved	RTH and small goiter T4 10× T3 10× TSH > 100×	Growth delay similar to TRα−/−; delayed endochondral ossification; impaired chondrocyte differentiation; reduced mineralization	Die at or near weaning	NR	311
TRα1−/−TRβ−/−	No TRα1, TRΔα1 or TRβ TRα2 and TRΔα2 preserved	RTH and large goiter T4 60× T3 60× TSH > 160× (GH/IGF-1 low)	Persistent growth retardation; delayed endochondral ossification; reduced mineralization	Reduced trabecular and cortical BMD GH treatment corrects growth but not ossification defect	NR	305–307
TRα2−/−TRβ−/−	No TRα2, TRΔα2 or TRβ	Mild hypothyroidism	Transient growth delay	NR	NR	309
	TRα1 and TRΔα1 overexpression	T4 0.7×
		T3 0.8×
		TSH normal
TRα0/0TRβ−/−	No TRα or TRβ	RTH and goiter T4 14× T3 13× TSH > 200× (GH/IGF-1 low)	More severe phenotype than TRα0/0; growth delay; delayed endochondral ossification; impaired chondrocyte differentiation; reduced mineralization	NR	NR	219, 313, 314
Pax8−/−TRα1−/−	No TRα1 or TRΔα1	No Thyroid	Growth retardation similar to Pax8−/−	Die by weaning	NR	315
	TRα2/TRΔα2 preserved	T4 undetectable
	Apo TRβ	T3 undetectable
	Maximal Tshr signaling	TSH NR
Pax8−/−TRα0/0	No TRα	No Thyroid	Growth retardation less than Pax8−/− and similar to TRα0/0β−/−; delayed endochondral ossification; mice survive to adulthood	NR	NR	314
	Apo TRβ	T4 undetectable
	Maximal Tshr signaling	T3 undetectable TSH > 400×
Pax8−/−TRβ−/−	No TRβ	No Thyroid	Growth retardation similar to Pax8−/−; severely delayed endochondral ossification	Die by weaning	NR	314
	Apo TRα	T4 undetectable
	Maximal Tshr signaling	T3 undetectable TSH > 400×
Deiodinase mutants
C3H/HeJ	80% reduction in D1 activity	T4 1.6× T3 normal rT3 3×	Not reported	NR	NR	294, 296
Dio1−/−	No Dio1	T4 1.4× T3 normal TSH normal rT3 4×	Normal growth	NR	NR	52, 288
Dio2−/−	No Dio2	T4 1–1.3×	Normal intramembranous and endochondral ossification	Reduced bone formation	Reduced T3 action in osteoblasts	60, 288, 536
		T3 normal		Increased mineralization
		TSH 3–15×		Brittle bones
		rT3 normal
Dio3−/−	No Dio3	Perinatal thyrotoxicosis Adult central hypothyroidism	Reduced body length	NR	NR	299, 300
Compound mutants
Dio1−/− Dio2−/−	No Dio1 or Dio2	T4 1.7× T3 normal TSH 15× rT3 6.5×	Normal growth	NR	NR	288
Transporter mutants
Mct8−/−	No Mct8	T4 0.7–0.3× T3 1–1.4× TSH 1–3× rT3 0.2×	NR	NR	NR	288, 289, 291, 292, 537
Mct10Y88*/Y88*	No Mct10	P21: T4 normal; T3 0.8× Adult: T4 and T3 normal	NR	NR	NR	290, 291
Oatp1c1−/−	No Oatp1c1	T4, T3 and TSH normal	NR	NR	NR	292, 293
Compound mutants			NR	NR
Mct8−/− Mct10Y88*/Y88*	No Mct8 or Mct10	P21, T4 0.6×; T3 1.6×. Adult, T4 normal; T3 3×	NR	NR	NR	291
Mct8−/− Oatp1c1−/−	No Mct10 or Oatp1c1	T4 0.3× T3 2× TSH 5×	Growth retarded after P16	NR	NR	292
Mct8−/− Dio1−/−	No Mct8 or Dio1	T4 1.4× T3 normal TSH 1.4× rT3 normal	Mild growth retardation	NR	NR	288
Mct8−/− Dio2−/−	No Mct8 or Dio2	T4 0.4× T3 1.7× TSH 50× rT3 0.2×	Mild growth retardation	NR	NR	288, 538
Mct8−/− Dio1−/− Dio2−/−	No Mct8, Dio1 or Dio2	T4 2.3× T3 1.4× TSH 100× rT3 2×	Growth retarded	NR	NR	288

Abbreviation: NR, not reported.