N‐cadherin Regulation of Bone Growth and Homeostasis Is Osteolineage Stage–Specific

Abstract

N-cadherin inhibits osteogenic cell differentiation and canonical Wnt/β-catenin signaling in vitro. However, in vivo both conditional Cdh2 ablation and overexpression in osteoblasts lead to low bone mass. We tested the hypothesis that N-cadherin has different effects on osteolineage cells depending upon their differentiation stage. Embryonic conditional osteolineage Cdh2 deletion in mice results in defective growth, low bone mass and reduced osteoprogenitor number. These abnormalities are prevented by delaying Cdh2 ablation until 1 month of age, thus targeting only committed and mature osteoblasts, suggesting they are the consequence of N-cadherin deficiency in osteoprogenitors. Indeed, diaphyseal trabecularization actually increases when Cdh2 is ablated postnatally. The sclerostin-insensitive Lrp5A214V mutant, associated with high bone mass, does not rescue the growth defect, but it overrides the low bone mass of embryonically Cdh2 deleted mice, suggesting N-cadherin interacts with Wnt signaling to control bone mass. Finally, bone accrual and β-catenin accumulation after administration of an anti-Dkk1 antibody are enhanced in N-cadherin deficient mice. Thus, while lack of N-cadherin in embryonic and perinatal age is detrimental to bone growth and bone accrual, in adult mice loss of N-cadherin in osteolineage cells favors bone formation. Hence, N-cadherin inhibition may widen the therapeutic window of osteoanabolic agents.

Osterix-Cre marks distinct subsets of CD45- and CD45+ stromal populations in extra-skeletal tumors with pro-tumorigenic characteristics

“…To determine whether osteolineage cells may be present in the TME, we crossed the established tetracycline-dependent Tg(Sp7-tTA,tetO-EGFP/cre)1Amc/J (Osx-cre) to the B6.Cg-Gt(ROSA)26Sortm9(CAG-tdTomato)Hze/J (TdT) to generate the Osx-cre;TdT reporter mouse model ( Rodda and McMahon, 2006 ). When constitutively activated, TdT marks the entire osteolineage, including bone surface osteoblasts, osteocytes and bone marrow cells with mesenchymal stem and osteoprogenitor cell features; while delaying Osx-cre expression until postnatally restricts TdT targeting to committed osteoblasts and osteocytes ( Mizoguchi et al, 2014 ; Fontana et al, 2017 ). Therefore, Osx-cre;TdT mice and control animals carrying only the TdT transgene (WT;TdT) were kept on standard chow to allow constitutive embryonic transgene activation, or fed a doxycycline (doxy)-containing diet until weaning to suppress transgene activation until one month of age ( Figure 1A ).…”

“…Therefore, Osx-cre;TdT mice and control animals carrying only the TdT transgene (WT;TdT) were kept on standard chow to allow constitutive embryonic transgene activation, or fed a doxycycline (doxy)-containing diet until weaning to suppress transgene activation until one month of age ( Figure 1A ). We previously reported that doxy-fed mice display less than 1% of spontaneous recombination in the bone residing osteoblasts at weaning, but full transgene activation 1 month thereafter ( Fontana et al, 2017 ).…”

“…Because TdT OSX + cells normally reside in the bone microenvironment ( Fontana et al, 2017 ; Strecker et al, 2013 ), we next examined bone sections from 8 week old doxy-fed Osx-cre;TdT reporter mice, naïve or bearing soft tissue B16-F10 or PyMT tumors. We confirmed presence of TdT OSX + cells on the surface of cortical and trabecular bone, TdT OSX + osteocytes, and also abundant staining in the bone marrow.…”

N-cadherin in cancer metastasis, its emerging role in haematological malignancies and potential as a therapeutic target in cancer

“…In development, N-cadherin plays an important role in morphogenetic processes during the formation of cardiac and neural tissues, and is involved in osteogenesis, skeletal myogenesis and maturation of the vasculature [ 28 – 32 ]. In adulthood, N-cadherin is expressed by numerous cell types including neural cells, endothelial cells, stromal cells and osteoblasts, and is integral to synapse function, vascular stability and bone homeostasis [ 30 , 33 – 36 ]. While N-cadherin is typically absent or expressed at low levels in normal epithelial cells, the aberrant expression of N-cadherin in epithelial cancer cells is a well-documented feature of epithelial malignancies, such as breast, prostate, urothelial and pancreatic cancer, and is associated with disease progression [ 37 – 40 ].…”

Dorsal root ganglion neurons regulate the transcriptional and translational programs of osteoblast differentiation in a microfluidic platform

“…A recent in vivo study described a dual action of this protein on osteolineage cells depending upon their differentiation level. The authors demonstrated that N-cadherin maintains the pool of osteoprogenitor and stem cells and prevents the osteoblast differentiation of lineage-committed cells and function of mature osteoblasts 53 . In our research, we detected an increase of N-cadherin expression in MSCs cocultured with DRG neurons for 4 days, followed by a decrease three days later.…”