Bone Abstracts

We have shown that genetic ablation of Cdh2 (N−cadherin gene) in osteolineage cells results in osteopenia and decreased osteoprogenitor number. Paradoxically, others have shown that mice overexpressing Cdh2 in osteoblasts are also osteopenic; an action linked to a negative effect of N−cadherin (Ncad) on Wnt signaling, via sequestration of low density lipoprotein receptor−related protein−5 or 6 (Lrp5/6) and Axin. We hypothesize that Ncad has different effects on osteolineage cells depending on their differentiation stage: it supports mesenchymal and progenitor stem cells (MSPC), but restrains mature osteoblast activity. Conditional Cdh2 ablation in Osx+ cells, which targets perinatal MSPC and osteoblasts, confirmed low trabecular bone mass (BV/TV by μCT), but also revealed significantly reduced body weight and size at age 2 months (20−25% and 15−20% vs wild type, respectively, P<0.05). However, delaying Cdh2 ablation until P28 (when Osx1 marks committed osteogenic cells but not MSPC) by doxycycline suppression of the Tet−sensitive Osx1−Cre transgene prevented the osteopenia and growth defect. In fact, trabecularization of the diaphyses was significantly larger in post−natally Cdh2 ablated mice (P<0.05), consistent with a negative action of Ncad in more mature osteogenic cells. Supporting the hypothesis that Ncad maintains MSPC, bone mass and osteoprogenitor number were also reduced upon early Cdh2 ablation by Prx1−Cre. Conversely, introduction of one Dkk1−resistant Lrp5 mutation (Lrp5^A214V) associated with high bone mass, in cKO^Osx1 background completely rescued the osteopenia but not the early growth defect. Indeed, cKO^Osx1; Lrp5^A214V compound mutant mice in the first month of life were 20−25% lower in weight than Lrp5^A214V mice, but as adults displayed high bone mass (BV/TV by μCT). Thus, Ncad is involved in MSPC maintenance and early post-natal skeletal growth; the latter action is independent of Ncad restraining effect on Wnt signaling. Interference with Ncad in adults may result on bone anabolism without potential detrimental effects on osteoprogenitors.