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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 ( Ctnnb1   f/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  Ctnnb1   f/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  Ctnnb1   f/f   ;CtsKCre  animals combines a cell-autonomous effect in the mature osteoclast with indirect effects due to the additional targeting of osteoblastic cells.

CathepsinKCre mediated deletion of βcatenin results in dramatic loss of bone mass by targeting both osteoclasts and osteoblastic cells