Table 1.

Mouse models of TGF-β and BMP signaling in bone.

Classification	Gene	KO/CKO/Tg/knock-in	Phenotype	References
TGF-β ligands	Tgfb1	KO	Early death (1 month)	88
		Tgfb1−/−Rag2−/−	Reduced bone density; OB↓	152
		Col1α1 Prom-Tgfb1 H222D Tg (1)	Diaphyseal thickening, fluctuating bone volume, increased bone remodeling, prone to fracture; OB↑; OC↑	152
		Col1α1 Prom-Tgfb1 H222D Tg	Knee and temporomandibular joint osteoarthritis↑	221,222
	Tgfb2	KO	Perinatal mortality; neural arch defect; bifurcated sternum; shortened radius and ulna	85
	Tgfb3	KO	Die within 20 h of birth; failure of the palatal shelves to fuse leading to cleft palate	86,87
BMP ligands	Bmp2	Col2α1-CreER	Severe chondrodysplasia; shortened stature and limbs; chondrocyte proliferation↓ & hypertrophy↓	50
		Prx1-Cre	Normal limb patterning	51
	Bmp7	KO	Die at birth; skull base defects; rib & sternum malformation; hindlimb polydactyly	326
	Bmp7, Alk6	DKO	Malformed and shortened appendicular bones compared to Bmp7−/−	25
	Bmp2, 7	Prx1-Cre;Bmp2f/f;Bmp7−/−	Slightly diminished appendicular skeleton; missing the last phalanx in digit III; malformed fibulae	51
	Bmp4	Col2α1-CreER	Mild chondrodysplasia	50
		Prx1-Cre	Polydactyly	51,52
	Bmp2, 4	Col2α1-CreER	Severe chondrodysplasia; severely shortened and malformed or missing long bone skeleton element & fused joints; chondrocyte proliferation↓ & hypertrophy↓	50
		Prx1-Cre	Polydactyly; complete syndactyly; delayed mineralization; chondrogenesis ↓ ; osteogenesis↓	51
	BMP3/GDF10	Col1 Prom-Bmp3 Tg	Late hypertrophic chondrocyte differentiation↓; thinner cortical bone; mineralization ↓ ; rib fracture	115
		KO	Increased bone density	28
	Bmp14/GDF5	bpJ (2)	Normal axial bones; shortened limbs and digits; missing joints of autopods; missing phalange elements	25,327
			No delay in fracture healing	328
			Increased joint damage in collagen-induced arthritis; reduced bone density	329
	GDF5, Alk6	bpJ/bpJ;Alk6−/−	Same as bpJ	25
Type I receptors	Alk2/Acvr1	Col2α1-Cre	Shortened cranial base; hypoplastic cervical vertebrae	49
		Osx-Cre	Mandibular bone density ↓ ; OB ↓ ; sRANKL ↑ ; OC↑	113
		Q207D Tg	Fibrodysplasia ossificans progressive	127,130,132
		Acvr1tnR206H/+;Tie2-Cre	Fibrodysplasia ossificans progressive	128
		R206H knock-in	Fibrodysplasia ossificans progressive	129
	Alk3/Bmpr1A	Col2α1-Cre	Split dorsal arches; shortened limbs; hypoplastic scapula; chondrodysplasia, chondrocyte proliferation ↓ , hypertrophy ↓ , terminal differentiation ↓ , and apoptosis↑	48,49,65
		Gdf5-Cre	Automatically develop osteoarthritis	330
		Col1α1-CreER	bone mass in long bones and ribs ↑ ; strength ↑ ; OC↓	148,149
		Sp7-Cre	Trabecular bone mass↑	147
		Dmp-Cre	Trabecular bone mass↑ (13-fold); OB proliferation↑ and activity ↓ ; RANKL & SOST ↓ ; OC↓	147,176
	Alk6/Bmpr1B	KO	Brachypodism; reduced phalangeal elements; the fusion of appendicular joints, similar to GDF5 mutant (bpJ) mice	25,48,49,65
		KO	Transient and gender-specific osteopenia caused by reduced osteogenesis from MSCs	331
		Col1α1 Prom-truncated Alk6 Tg	Reduced BMD and bone volume; reduced osteoblast and osteoclast number	332
	Alk3, Alk6	Col2α1-Cre;Alk3f/f;Alk6+/−	Phenotype resembling and more severe than Alk3 CKO mice	48,65
		Col2-Cre;Alk3f/f;Alk6−/−	Severe defects in cartilage formation and skeletogenesis	48
	Alk2, Alk3	Col2-Cre	Malformed axis skeleton (vertebra, cervical and thoracic regions); more severe appendicular defects than Alk3 CKO mice	49
	Alk2, Alk6	Col2-Cre;Alk2f/f;Alk6−/−	More severe axis and appendicular defects than each single KO	49
	Alk5/TGFBR1	Dermo-Cre	Short and wide long bones, ectopic cartilaginous protrusions, reduced bone volumes	83
		Col2α1 Prom-Alk5 DN Tg	Elongated limbs; chondrocyte proliferation↑	68
		Col2α1-CreERT	Automatic osteoarthritis	208,333
Type II receptors	Tgfbr2	Nestin-CreER	Knee osteoarthritis↓	221
		ColX-Cre	Delayed chondrocyte terminal differentiation; impeded mineralization	84
		Prx-Cre	Die at birth; reduced periodontal and frontal bone; shortened limbs; split sternum; autopod joint fusion; reduced mineralization; chondrocyte proliferation↓ & hypertrophy↑	78,81
		Col2α1-Cre	Survive; neural arch defect; missing/incomplete intervetebral discs; progressive reduction in long bone length	79,80
		Sp7-Cre (Dox)	Early death (1 M); reduced body size; reduced bone volume; increased bone marrow adipose tissue; disrupted molar tooth formation; OB↓	157,334
		Ocn-Cre	bone density ↑ ; OB ↑ ; OC↑	172
	Bmpr2	Prx1-Cre	Trabecular bone volume ↑ ; BFR ↑ ; selectively abolish Activin-Smad2/3 but not Bmp-Smad1/5/8 signaling	335
		Col1α1 Prom-Bmpr2 DN Tg	Dwarfism; delayed mineralization; bone volume ↓ ; no change in cortical bone	114
	ActRIIA/Acvr2A	Ocn-Cre	Trabecular bone volume↑	336
	ActRIIB/Acvr2B	KO	Late hypertrophic chondrocyte differentiation ↓ ; thinner cortical bone; mineralization ↓ ; rib fracture	115
		Ocn-Cre	Normal	336
	ActRIIA, ActRIIB	Ocn-Cre	Trabecular bone volume↑ like ActRIIA−/−	336
Canonical pathway	Smad1	Col1α1-Cre	Osteopenia; OB proliferation and differentiation↓	337
		Col2α1-Cre	Shortened growth plate; chondrocyte hypertrophy↓ and proliferation↓	68
	Smad1/5	Col2α1-Cre;Smad1f/f;Smad5+/−	Similar and more severe phenotype than Smad1 CKO	68
	Smad1/5	Col2α1-Cre	Chondrodysplasia; shortened limbs; thicker perichondrium; matrix production ↓ ; hypertrophy↓	69
	Smad8	KO	Normal	69
	Smad1/5/8	Col2α1-Cre;Smad1f/f;Smad5f/f;Smad8−/−	Absence of an axial skeleton; severely disorganized appendicular bones	69
	Smad2	Col2α1-Cre	Similar and more severe phenotype than Smad3 KO mice	89
	Smad2/3	Col2α1-Cre;Smad2f/f;Smad3−/−	Similar and more severe phenotype than Smad3 KO mice	89
	Smad3	KO	Postnatal dwarfism; expanded columnar and hypertrophic zone; chondrocyte proliferation↑ and hypertrophy↑	89
		KO	Knee and temporomandibular joint osteoarthritis	214,215
		KO	Osteopenia; OB and OCY apoptosis↑	156
	Smad4	Tbx18-Cre	Short limbs, chondrogenesis↓ & hypertrophy ↓ , missing stylopod	40
		Sp7-Cre (Dox)	Increased trabecular bone mass	147
		Sp7-Cre	Stunted growth; spontaneous fractures; increased trabecular bone volume; decreased BMD; a combination of features seen in osteogenesis imperfecta, cleidocranial dysplasia, and Wnt-deficiency syndromes	118
		Dmp-Cre	Increased trabecular bone mass (~2-fold)	147
		Col1α1-Cre	Increased trabecular bone mass; protection from tail suspension-induced bone loss; OB & OCY number ↑ ; OB & OCY apoptosis↓	178
		Ocn-Cre	Lower bone mass < 6-month, more bone mass > 7-month	177
		Ctsk-Cre	Reduced bone mass; OC↑	186
Non-canonical pathway	TAK1	Col2α1-CreER	Growth retardation; osteoarthritis markers ↑ ; no osteoarthritis histological signs	71
		Osx-Cre	Cleidocranial dysplasia (CCD)-like phenotype (clavicular hypoplasia and delayed fontanelle fusion); OB ↓ ; reduced cancellous and trabecular bone volume	116
		Col2α1-Cre	Shorter limbs; chondrocyte proliferation ↓ , survival↓ & hypertrophy ↓ ; failure to maintain interzone cells of the elbow joint	338
		Prx1-Cre	Widespread joint fusions; chondrocyte hypertrophy and proliferation	338
	p38	Ocn-Cre	OB activity and BFR ↓ ; reduced cancellous and trabecular bone volume	117
		Col2α1 Prom-p38DN Tg	Shortened limbs; knee joint osteoarthritis↑	210
		p38b−/−	A substantial decrease in long bone mineralization and a more modest effect on the calvarium	116
	MKKs	Mkk3−/−Mkk6+/− and Mkk3−/−	Similar phenotype to Tak1f/f;Osx-Cre mice	116
I-SMAD and ubiquitin-related regulation	Smad6	Col11α1 Prom-Smad6 Tg	Dwarfism and osteopenia; chondrocyte hypertrophy↓	279
		KO	Dwarfism; defects in axial and appendicular bones; delayed onset of hypertrophy	280
	Smad6;Smurf1	Col11α1::Tg	More severely delayed endochondral ossification than Smad6 Tg	279
	Smad7	ΔExon1	Osteopenia; BFR ↓ ; OC↑	282
		KO	Chondrocyte proliferation and hypertrophy ↓ ; shortened growth plate	339
		Prx1 Prom-Tg; Col11 Enh-Tg; Col11 Prom-Tg	Chondrodysplasia; mesenchymal condensation ↓ ; chondrocyte proliferation and hypertrophy↓	283
	Smurf1	KO	Bone mass ↑ ; BFR↑	286
		Col1α1 Prom-Tg	Osteopenia; BFR↓	285
	Smurf2	Col2α1 Prom-Tg	Osteoarthritis; intervertebral disc degeneration	291,292
		KO	Protection from age-related and DMM-induced osteoarthritis	293
		KO	Osteopenia ↓ ; OC↑	296
		KO	Enhanced BMP-induced ectopic bone formation	294
	PLEKHO1	Osterix-Cre	Protection from age-related bone loss	289
		Osterix Prom-Tg	Age-related bone loss	289
	NEDD4	Col1α1-Cre	Bone mass ↓ ; OB↓	298
		Col1α1 Prom-Tg	Bone mass ↑ ; OB↑	298
	Jab1	Osx-Cre	Dwarfism; trabecular bone mass↓	303
Antagonists	Noggin	Ocn Prom-Tg	Osteopenia; BFR↓	250,253
		Ocn-Cre	Osteopenia	254
		KO	Hyperplasia of cartilage; joint development failure; multiple skeletal defects related to neural tube and somite patterning (failure of neural tube closure, broad club-shaped limbs, loss of caudal vertebrae, a shortened body axis, and retention of a small vestigial tail)	66,67
	Grem1	Ocn-Cre	Bone mass ↑ ; BFR↑	258
		Ocn Prom-Tg	Bone fractures; bone mass ↓ ; BFR↓	259
	FS	Tg	Bone mass ↓ ; bone fractures	262
Co-receptors	β-glycan	KO	Defective palate development with OB↓	267
	Nrps	KO	Bone mass ↓ ; OB ↓ ; OC↓	268
	Neogenin	KO	Elongated growth plate; chondrocyte proliferation & apoptosis ↓ ; endochondral ossification↓	276
Other regulators	Tmem53	KO	Sclerosing bone	308
	Endofin	Col1 Prom-Endofin F872A Tg	Bone mass ↑ ; BFR↑	304

Prom promoter, Enh Enhancer, Tg transgenic, KO knockout, CKO conditional knockout, BFR bone formation rate, OB osteoblast, OC osteoclast, OCY osteocyte, BMD bone mineral density, DN dominant negative

Annotations.

(1) Col1α1 Prom-Tgfb1 H222D Tg, transgenic mice carrying a Tgfb1 H222D mutant under the control of Col1α1 promoter; Tgfb1 H222D mutant is found in human Camurati-Engelmann disease (CED). This mouse model is also named as Tgfb1-CED or CED mice.

(2) Bp^J is the mouse model carrying Gdf5 mutation (bp-J allele) which occurs spontaneously in the A/J strain. Bp is short for brachypodism.