Loss of Cbl–PI3K interaction in mice prevents significant bone loss following ovariectomy

•Cbl family of protein plays distinct roles during normal and pathological bone remodeling.•Mice lacking Cbl–PI3K interaction due to tyrosine to phenylalanine mutation (Y737F, CblYF/YF mice) are protected from significant bone loss.•Upon ovariectomy CblYF/YF mice demonstrate uncoupling of osteoclast and osteoblast functions, preventing bone loss up on acute estrogen withdrawal.

Cbl and Cbl-b are E3 ubiquitin ligases and adaptor proteins, which perform regulatory roles in bone remodeling. Cbl −/− mice have delayed bone development due to decreased osteoclast migration. Cbl-b −/− mice are osteopenic due to increased bone resorbing activity of osteoclasts. Unique to Cbl, but not present in Cbl-b, is tyrosine 737 in the YEAM motif, which upon phosphorylation provides a binding site for the regulatory p85 subunit of PI3K. Substitution of tyrosine 737 with phenylalanine (Y737F, CblYF/YF mice) prevents Y737 phosphorylation and abrogates the Cbl–PI3K interaction. We have previously reported that CblYF/YF mice had increased bone volume due to defective bone resorption and increased bone formation. Here we show that the lumbar vertebra from CblYF/YF mice did not have significant bone loss following ovariectomy. Our data also suggests that abrogation of Cbl–PI3K interaction in mice results in the loss of coupling between bone resorption and formation, since ovariectomized CblYF/YF mice did not show significant changes in serum levels of c-terminal telopeptide (CTX), whereas the serum levels of pro-collagen type-1 amino-terminal pro-peptide (P1NP) were decreased. In contrast, following ovariectomy, Cbl −/− and Cbl-b −/− mice showed significant bone loss in the tibiae and L2 vertebrae, concomitant with increased serum CTX and P1NP levels. These data indicate that while lack of Cbl or Cbl-b distinctly affects bone remodeling, only the loss of Cbl–PI3K interaction protects mice from significant bone loss following ovariectomy.