N-cadherin and cadherin 11 modulate postnatal bone growth and osteoblast differentiation by distinct mechanisms.
We have previously shown that targeted expression of a dominant-negative truncated form of N-cadherin (Cdh2) delays acquisition of peak bone mass in mice and retards osteoblast differentiation; whereas deletion of cadherin 11 (Cdh11), another osteoblast cadherin, leads to only modest osteopenia. To determine the specific roles of these two cadherins in the adult skeleton, we generated mice with an osteoblast/osteocyte specific Cdh2 ablation (cKO) and double Cdh2(+/-);Cdh11(-/-) germline mutant mice. Age-dependent osteopenia and smaller diaphyses with decreased bone strength characterize cKO bones. By contrast, Cdh2(+/-);Cdh11(-/-) exhibit severely reduced trabecular bone mass, decreased in vivo bone formation rate, smaller diaphyses and impaired bone strength relative to single Cdh11 null mice. The number of bone marrow immature precursors and osteoprogenitor cells is reduced in both cKO and Cdh2(+/-);Cdh11(-/-) mice, suggesting that N-cadherin is involved in maintenance of the stromal cell precursor pool via the osteoblast. Although Cdh11 is dispensable for postnatal skeletal growth, it favors osteogenesis over adipogenesis. Deletion of either cadherin reduces β-catenin abundance and β-catenin-dependent gene expression, whereas N-cadherin loss disrupts cell-cell adhesion more severely than loss of cadherin 11. Thus, Cdh2 and Cdh11 are crucial regulators of postnatal skeletal growth and bone mass maintenance, serving overlapping, yet distinct, functions in the osteogenic lineage.
Di Benedetto
Adriana
A
Division of Bone and Mineral Diseases, Department of Internal Medicine, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8301, St Louis, MO 63110, USA.
Watkins
Marcus
M
Grimston
Susan
S
Salazar
Valerie
V
Donsante
Christine
C
Mbalaviele
Gabriel
G
Radice
Glenn L
GL
Civitelli
Roberto
R
D000818:Animals; D001696:Biomechanical Phenomena; D015519:Bone Density; D001842:Bone and Bones / Q000166:cytology* / Q000378:metabolism*; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D002448:Cell Adhesion; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D015151:Immunoblotting; D051379:Mice; D018345:Mice, Knockout; D010006:Osteoblasts / Q000166:cytology* / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D015820:Cadherins; C086960:osteoblast cadherin