Table 1.
Summary of bone phenotypes in mouse models of altered Wnt signaling in osteoblast lineage cells and the germline.
| Gene | KO/CKO/Tg/CKI | Cre line | Bone phenotype(s) | References |
|---|---|---|---|---|
| APC | CKO | OCN-Cre | Early postnatal lethality, osteopetrosis, increased trabecular bone density, few osteoclasts, elevated Opg | Holmen et al., 2005 |
| CKO | Col2a1-Cre | Early postnatal lethality, reduced mineralization at E14.5, increased mineralization at E16.5 and in ribs | Miclea et al., 2009 | |
| Axin2 | KO | Germline | Craniosynostosis, increased BMD | Yu et al., 2005 |
| Ctnnb1 (β-Catenin) | CKO | Wnt1-Cre | Embryonic lethal, block in prechondrocyte condensation and craniofacial development | Brault et al., 2001 |
| CKO | Prx1-Cre | Lack of mineralization in head and distal skeletal elements, enhanced chondrogenesis, lower osteoblastogenesis | Hill et al., 2005 | |
| CKO | Dermo1-Cre | Shortened limbs, twisted body axis, diminished intramembranous and endochondral bone formation, ectopic cartilage | Day et al., 2005; Hu et al., 2005 | |
| CKO | Osx1-Cre | Lack of cranial ossification, increased chondrogenesis | Rodda et al., 2005 | |
| CKO | Col2a1-Cre | Ectopic cartilage in long bones, normal intramembranous bone | Day et al., 2005 | |
| CKO | 2.3Col1a1-Cre | Reduced bone mass, increased osteoclast numbers, decreased Opg | Glass et al., 2005 | |
| CKO | Ocn-Cre | Early postnatal lethality, reduced cortical and trabecular bone density, increased osteoclast numbers | Holmen et al., 2005 | |
| CKO | Dmp1-Cre | Premature postnatal lethality, impaired cortical and trabecular bone mass, increased osteoclast number and activity, decreased Opg levels | Kramer et al., 2010a | |
| CKI/GOF | Prx1-Cre: exon3 | Early postnatal lethality, no bone formation | Hill et al., 2005 | |
| CKI/GOF | Osx1-Cre: exon3 | Embryonic lethality, excessive premature ossification | Rodda et al., 2005 | |
| CKI/GOF | 2.3Col1a1-Cre: exon3 | Premature postnatal lethality, failed tooth eruption, increased ossification, decreased osteoclast numbers and function, normal osteoblast numbers, rib osteomata | Glass et al., 2005 | |
| Dkk1 | Het | Germline | High bone mass inversely proportional to Dkk1 concentration in hypomorphic animals | Morvan et al., 2006; MacDonald et al., 2004, 2007 |
| Tg | 2.3 and 3.6Col1a1 | Low bone mass, decreased osteoblast number, reduced serum osteocalcin levels, lower matrix mineralization | Li et al., 2006 | |
| Tg | 2.3Col1a1 | Osteopenia, reduced bone formation, normal PTH responsiveness | Fleming et al., 2008; Guo et al., 2010; Yao et al., 2011 | |
| Dkk1d | Hypomorphic mutation | Increased bone mass that is inversely proportional to Dkk1 expression, distal forelimb postaxial polysyndactyly | MacDonald et al., 2007 | |
| Dkk2 | KO | Germline | Low bone mass | Li et al., 2005 |
| Fzd9 | KO | Germline | Osteopenia, decreased bone formation | Albers et al., 2008 |
| Gsk3β | Het KO | Germline | Increased trabecular bone mass | Kugimiya et al., 2008; Noh et al., 2009 |
| Krm1/2 | DKO | Germline | Increased BMD | Ellwanger et al., 2008 |
| Krm2 | KO | Germline | High bone mass at 24 weeks, increased bone formation | Schulze et al., 2010 |
| Krm2 | Tg | 2.3Col1a1 | Osteoporosis, decreased bone formation, reduced cortical strength, reduced Opg expression, and increased bone resorption | Schulze et al., 2010 |
| Lef1 | Het KO | Germline | Reduced bone formation in females only | Noh et al., 2009 |
| KO | Germline | Reduced bone mass in all KO and Het mice | JJW et al., unpublished | |
| Lef1ΔN | Tg | 2.3Col1 | Increased trabecular bone mass | Hoeppner et al., 2010 |
| Lrp4 | Lrp4ECD | Hypomorph | Reduced BMD, increased bone turnover | Choi et al., 2009 |
| Lrp5 | KO | Germline | Decreased bone mass | Fujino et al., 2003; Kato et al., 2002 |
| CKO | 2.3Col1-Cre | Normal vertebral bone mass | Yadav et al., 2008 | |
| CKO | Dermo1-Cre | Normal vertebral bone mass | Yadav et al., 2010 | |
| CKO | Dmp1-Cre | Decreased trabecular bone mass and cortical strength | Cui et al., 2011 | |
| Tg | Rat 3.6Col1-HBM G171V | Increased bone mass and strength | Akhter et al., 2004; Babij et al., 2003 | |
| CKI/GOF | 2.3Col1-Cre: HBM G171V cDNA | Normal vertebral bone mass and bone formation rates | Yadav et al., 2008 | |
| CKI/GOF | Dmp1-Cre: HBM G171V or A214V | Increased trabecular bone mass, bone strength, and bone formation rates in distal femur and L5 | Cui et al., 2011 | |
| CKI/GOF | Prx1-Cre: HBM G171V | Increased bone mass in limbs, but not vertebrae | Cui et al., 2011 | |
| CKI/GOF | Villin-Cre: HBM G171V | Increased vertebral bone mass and bone formation rates | Yadav et al., 2008 | |
| CKO | Villin-Cre | Decreased vertebral bone mass, bone formation rates and osteoblast numbers | Yadav et al., 2008 | |
| CKI/GOF | Vil1-Cre: HBM G171V or A214V | Normal bone mass | Cui et al., 2011 | |
| CKO | Vil1-Cre | Normal bone mass | Cui et al., 2011 | |
| Lrp6 | Het KO | Germline | Decreased bone | Holmen et al., 2004 |
| Rs | Hypomorphic mutation | Decreased bone mineral density, no chance in osteoblast number, elevated Rankl expression, increased bone resorption | Kubota et al., 2009 | |
| Lrp5/6 | KO/Het | Germline | Decreased bone | Holmen et al., 2004 |
| Rspo2 | KO | Germline | Decreased ossification in distal phalanges and stunted fibula | Nam et al., 2007 |
| Sfrp1 | KO | Germline | Increased bone mass | Bodine et al., 2004 |
| Tg | Sfrp1 | Decreased bone mass | Yao et al., 2010 | |
| Sfrp4 | Tg | 2.3Col1a1 | Low bone mass, fewer osteoblasts; LiCl rescued these defects | Nakanishi et al., 2008 |
| Tg | Serum amyloid P | Decreased bone mass | Cho et al., 2010 | |
| Sclerostin (Scl, Sost) | KO | Germline | Increased bone mass | Balemans et al., 2003; Krause et al., 2010 |
| Tg | Ocn + APO E | Osteopenia | Winkler et al., 2003 | |
| Tg | SOST | Osteopenia | Loots et al., 2005 | |
| Sostdc1 (Wise) | KO | Germline | Supernumerary teeth, bone phenotype not determined | Ahn etal., 2010; Kassai et al., 2005; Murashima-Suginami et al., 2008 |
| Tcf7 (Tcf1) | KO | Germline | Lower bone mass (modest), increased bone resorption | Glass et al., 2005 |
| Wif1 | KO | Germline | Normal skeletal development, accelerated radiation-induced osteosarcoma formation | Kansara et al., 2009 |
| Tg | 2.3Col1a1 | Normal bone, depletion of hematopoietic stem cells | Schaniel et al., 2011 | |
| Wls (Gpr177) | CKO | Wnt1-Cre | Craniofacial defects, defective anterior–posterior axis formation | Carpenter et al., 2010; Fu et al., 2011 |
| Wnt3a | Het KO | Germline | Reduced BMD | Takada et al., 2007 |
| Wnt5a | Het KO | Germline | Reduced BMD, increased adipogenesis | Takada et al., 2007 |
| Wnt7b | KO | Germline | No defects in skeletal development | Rodda et al., 2005 |
| Wnt10b | KO | Germline | Reduced BMD, increased adipogenesis | Bennett et al., 2005, 2007; Stevens et al., 2010 |
| Tg | Fabp4 | Increased BMD | Bennett et al., 2005 | |
| Tg | Ocn | Increased BMD | Bennett et al., 2007 | |
| Wnt14 | Tg | Col2a1 | High expression blocked endochondral bone formation, lower transgene expression promoted chondrocyte maturation and enhanced endochondral bone formation | Day et al., 2005 |
| Wtx | KO | Germline | Sclerosis, increased osteoblastogenesis, but delayed mineralization | Moisan et al., 2011 |
| CKO | Prx1-Cre | Bone overgrowth, reduced marrow adiposity | ||
| CKO | Osx1-Cre | Increased cortical and trabecular bone mineralization | ||
| CKO | Col2a1 | Normal skeleton | ||
| CKO | Ocn-Cre | Normal skeleton |
BMD: bone mineral density; CKI: conditional knock-in; CKO: conditional knockout mouse; GOF, gain of function; HBM, high bone mass mutations; Het: heterozygous knockout mouse; KO: global knockout; DKO: double global knockout; Opg: osteoprotegerin; Rs: ringelschwanz hypomorphic Lrp6 mutation; Tg: transgenic.