Table 1.
Mouse Model of Wnt ligands and its signaling effectors regulate skeletogenesis
| Model | Phenotype | References | ||||||
|---|---|---|---|---|---|---|---|---|
| Bone resorption | Bone formation | Chondrocyte differentiation | BMD change | Cortical thickness | Trabecular thickness | Others Features | ||
| Functional Group: Wnt ligands | ||||||||
| Wnt3a+/− | nd | ↓ | nd | ↓ | nd | Number (down) | Low bone mass | (32) |
| Wnt4 transgenic (Col2a1-cre) | nd | ↓ | Increased hypertrophic chondrocytes | — | nd | nd | Dwarfism | (29) |
| Wnt5a+/− | nd | ↓ | nd | ↓ | nd | Number (down) | Low bone mass | (32) |
| Wnt5a transgenic (Col2a1-cre) | nd | ↓ | ↓ | nd | nd | nd | Short long bones and reduce ossification | (30) |
| Wnt5b transgenic (Col2a1-cre) | nd | ↓ | ↓ | nd | nd | nd | Open skull, short long bones and reduce ossification | (30) |
| Wnt7 conditional knockout (dermo-cre) | nd | ↓ | ↓ | nd | nd | nd | Bone development defects | (44) |
| Wnt9a/Wnt14−/− | nd | nd | ↓ | ↓ | nd | nd | Reduced the length of long bone and lead to ectopic differentiation of cartilage | (28) |
| Wnt9a/Wnt14 transgenic | Nd | nd | ↓ | ↑ | nd | nd | Enhanced ossification and reduced joint formation | (26) |
| Wnt10b−/− | — | ↓ | nd | ↓ | nd | Number (down) | Low bone mass | (34) |
| Wnt10b+/− | — | ↓ | nd | ↓ | nd | ↓ | Osteopenia and has less osteoprogenitors | (36) |
| Wnt10b transgenic (osteocalcin) | nd | ↑ | nd | ↑ | nd | ↑ | Increase mandibular bone, trabecular bone and delayed incisor development | (35) |
| Wnt10b transgenic (FABP4 promoter) | nd | ↑ | nd | ↑ | — | ↑ | Increased bone mass | (34) |
| Wnt16−/− | nd | nd | nd | ↓ | ↓ | — | Low bone mass and increase risk of fracture | (45) |
| Functional Group: Wnt receptors | ||||||||
| Fzd8−/− | ↑ | — | nd | ↓ | nd | ↓ | Low trabecular bone volume | (59) |
| Fzd9−/− | nd | ↓ | nd | ↓ | nd | Number (down) | osteopenia | (60) |
| Lrp4−/− | nd | nd | Disrupted | nd | nd | nd | Polysyndactyly, fused digital bones, and tooth development abnormalities | (288) |
| Lrp5−/− | — | ↓ | nd | ↓ | nd | nd | Low bone mass | (79) |
| Lrp5+/− | nd | ↓ | nd | ↓ | nd | nd | Low bone mass | (79) |
| Lrp5 conditional knockout (Dmp1-cre) | nd | ↓ | nd | ↓ | nd | nd | Low bone mass | (289) |
| Lrp5 a point mutation (A214V) | — | ↑ | nd | ↑ | ↑ | ↑ | Increased bone mass, bone strength and bone formation rate | (289, 290) |
| Lrp5 a point mutation (G171V) | — | ↑ | nd | ↑ | ↑ | ↑ | Increased bone mass, bone strength and bone formation rate | (289, 290) |
| Lrp6 a point mutation (R886W) | nd | nd | nd | ↓ | ↓ | Number (down) | Delayed ossification at birth and osteoporosis in adult | (82) |
| Functional Group: Wnt antagonist | ||||||||
| Dkk1+/− | — | ↑ | nd | ↑ | nd | ↑ | High bone mass | (90) |
| Dkk1 transgenic (Col1A1) | — | ↓ | nd | ↓ | ↓ | ↓ | Systemic osteopenia | (89) |
| Dkk2−/− | ↑ | ↓ | nd | ↓ | ↓ | ↓ | osteopenia | (97) |
| Sfrp1−/− | — | ↑ | nd | — | — | ↑ | Increase trabecular bone formation | (63) |
| Sfrp2−/− | nd | ↓ | ↓ | nd | nd | nd | Brachydactyly, mild mesomelic shortening and posterior soft-tissue syndactyly | (68) |
| Sfrp4 transgenic (col1a1) | nd | ↓ | nd | ↓ | nd | Number (down) | Low bone mass | (70) |
| Sost transgenic (human SOST) | — | ↓ | ↓ | ↓ | ↓ | ↓ | Low bone mass | (108) |
| Functional Group: Effectors in cytoplasm | ||||||||
| GSK3β−/+ | ↑ | ↑ | nd | ↑ | ↑ | ↑ | High bone mass | (291) |
| GSK3α−/−; GSK3β+/− | nd | ↓ | ↓ | nd | nd | nd | Dwarfism with significantly shortened long bone and vertebra. | (139) |
| Axin2−/− | nd | ↑ | ↑ | ↑ | nd | nd | Craniosynostosis | (133, 134) |
| Apc−/− conditional knockout (osteocalcin) | ↓ | ↑ | nd | ↑ | nd | Nd | Increased bone deposition and a disappearance of osteoclasts | (128) |
| Apc conditional knockout (Col2a1) | nd | ↓ | ↓ | ↓ | nd | nd | Perinatally lethal; craniofacial abnormalities, short trunk, an incomplete closure of both thoracic and abdominal cavities | (127) |
| Functional Group: Transcription regulation | ||||||||
| β-catenin conditional knock out (Prx) | — | ↓ | ↓ | ↓ | nd | nd | Bone development defect. | (146) |
| β-catenin conditional knockout (Dermo1) | ↓ | nd | ↑ | nd | nd | nd | Long bone shortened, thickened, bowed, and ectopic cartilage formation | (148) |
| β-catenin conditional knockout (Col2a1) | nd | ↓ | ↓ | nd | nd | nd | Died shortly after birth. Limbs were shortened and head was dome shaped. Joints between the future tarsal bones were either missing or incompletely formed. | (26, 147) |
| β-catenin conditional knockout (Col1a1) | ↑ | — | nd | ↓ | nd | nd | Low bone mass | (153) |
| β-catenin conditional knockout (Osterix) | nd | ↓ | ↓ | nd | nd | nd | Lack the membranous bone of cranial ossification center and complete loss of bone deposition | (190) |
| β-catenin conditional knockout (osteocalcin) | ↑ | nd | nd | ↓ | ↓ | ↓ | Occasionally paralysis, consistent with osteoporotic-related fracture | (128) |
| β-catenin+/− conditional knockout (PPARγ) | ↑ | — | nd | ↓ | ↓ | ↓ | Osteoporosis | (154) |
| β-catenin conditional knockout (PPARγ) | ↓ | — | nd | ↑ | ↑ | ↑ | Osteopetrosis | (154) |
| β-catenin transgenic (Prx) | nd | ↓ | ↓ | nd | nd | nd | Limbs contain only tiny remnants of skeletal elements and skull bones are lost. | (146) |
| β-catenin transgenic (Col2 A1) | nd | nd | ↓ | nd | nd | nd | Perinatal lethal, ectopic joint formation and endochondral ossification | (26) |
| β-catenin transgenic (Col1A1) | ↓ | — | nd | ↑ | nd | nd | osteopetrosis | (153) |
| β-catenin+/− transgenic (Osterix) | nd | ↑ | — | nd | nd | nd | Died at birth, shorter limbs, intense and broader ossification center in long bone. | (190) |
| β-catenin+/− transgenic (PPARγ) | ↓ | — | nd | ↑ | ↑ | ↑ | Osteopetrosis | (154) |
| Tcf1−/− | ↑ | — | nd | ↓ | nd | nd | Low bone mass | (153) |
| Tcf1 Dominant negative (Col2a1) | nd | ↓ | ↓ | nd | nd | nd | Dwarfism, retarded mineralization in limbs, ribs and vertebrae | (160) |
| Lef1ΔN Transgenic (Col1a1) | nd | ↑ | nd | ↑ | nd | ↑ | High bone mass | (161) |
| β-catenin+/− conditional knockout (Col1A1); Tcf+/− | ↑ | — | nd | ↓ | nd | nd | Low bone mass | (153) |
BMD, bone mineral density; ↑ promotion; ↓ inhibition; — not changed; nd, not detected