CathepsinKCre mediated deletion of βcatenin results in dramatic loss of bone mass by targeting both osteoclasts and osteoblastic cells.
It is well established that activation of Wnt/βcatenin signaling in the osteoblast lineage leads to an increase in bone mass through a dual mechanism: increased osteoblastogenesis and decreased osteoclastogenesis. However, the effect of this pathway on the osteoclast lineage has been less explored. Here, we aimed to examine the effects of Wnt/βcatenin signaling in mature osteoclasts by generating mice lacking βcatenin in CathepsinK-expressing cells (Ctnnb1f/f;CtsKCre mice). These mice developed a severe low-bone-mass phenotype with onset in the second month and in correlation with an excessive number of osteoclasts, detected by TRAP staining and histomorphometric quantification. We found that WNT3A, through the canonical pathway, promoted osteoclast apoptosis and therefore attenuated the number of M-CSF and RANKL-derived osteoclasts in vitro. This reveals a cell-autonomous effect of Wnt/βcatenin signaling in controlling the life span of mature osteoclasts. Furthermore, bone Opg expression in Ctnnb1f/f;CtsKCre mice was dramatically decreased pointing to an additional external activation of osteoclasts. Accordingly, expression of CathepsinK was detected in TRAP-negative cells of the inner periosteal layer also expressing Col1. Our results indicate that the bone phenotype of Ctnnb1f/f;CtsKCre animals combines a cell-autonomous effect in the mature osteoclast with indirect effects due to the additional targeting of osteoblastic cells.
Instituto de Investigación Marqués de Valdecilla, IDIVAL, Cardenal Herrera Oria s/n. 39011 Santander, Spain.
Paula
P
Ruiz
Instituto de Investigación Marqués de Valdecilla, IDIVAL, Cardenal Herrera Oria s/n. 39011 Santander, Spain.|Department of Internal Medicine, HUMV, Hospital Universitario Marqués de Valdecilla, Avenida de Valdecilla s/n, 39008 Santander, Cantabria, Spain.
Marta
M
Martin-Millan
Instituto de Biomedicina y Biotecnología de Cantabria, IBBTEC (CSIC-SODERCAN-Universidad de Cantabria). Albert Einstein 22, 39011 Santander, Spain.
M C
MC
Gonzalez-Martin
Center for Osteoporosis and Metabolic Bone Diseases, University of Arkansas for Medical Sciences and the Central Arkansas Veterans Healthcare System, Little Rock, AR, USA.
Maria
M
Almeida
Instituto de Investigación Marqués de Valdecilla, IDIVAL, Cardenal Herrera Oria s/n. 39011 Santander, Spain.|Department of Internal Medicine, HUMV, Hospital Universitario Marqués de Valdecilla, Avenida de Valdecilla s/n, 39008 Santander, Cantabria, Spain.|Departamento de Medicina y Psiquiatría. Facultad de Medicina. Universidad de Cantabria, Cardenal Herrera Oria, s/n. 39011 Santander, Spain.|Red Temática de Investigación Cooperativa en Envejecimiento y Fragilidad (RETICEF), Avenida de Valdecilla, s/n. Santander 39008, Spain.
Jesús
J
González-Macias
Instituto de Biomedicina y Biotecnología de Cantabria, IBBTEC (CSIC-SODERCAN-Universidad de Cantabria). Albert Einstein 22, 39011 Santander, Spain.|Departamento de Anatomía y Biología Celular, Facultad de Medicina, Universidad de Cantabria, Cardenal Herrera Oria, s/n. 39011 Santander, Spain.
Maria A
MA
Ros
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D015519:Bone Density; D001862:Bone Resorption / Q000000981:diagnostic imaging / Q000235:genetics / Q000378:metabolism*; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000378:metabolism; D056657:Cathepsin K / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation / Q000235:genetics; D002478:Cells, Cultured; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010006:Osteoblasts / Q000378:metabolism*; D010010:Osteoclasts / Q000378:metabolism*; D053244:Osteoprotegerin / Q000235:genetics / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000235:genetics; D055114:X-Ray Microtomography / Q000379:methods; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
D053244:Osteoprotegerin; D051176:beta Catenin; D056657:Cathepsin K; C534132:Ctsk protein, mouse