Epithelium-Derived Wnt Ligands Are Essential for Maintenance of Underlying Digit Bone

Abstract

Clinically, many nail disorders accompany bone deformities, but whether the two defects are causally related is under debate. To investigate the potential interactions between the two tissue types, we analyzed epithelial-specific β-catenin deficient mice, in which nail differentiation is abrogated. These mice showed regression of not only the nail plate but also of the underlying digit bone. Characterization of these bone defects revealed active bone resorption, which is suppressed by Wnt activation in osteoblast and osteoclast precursors. Furthermore, we found that Wntless (Wls) expression, essential for Wnt ligand secretion, was lacking in the β-catenin deficient nail epithelium and that genetic deletion of Wls in the nail epithelium led to the lack of Wnt activation in osteoblast and osteoclast precursors and subsequently led to defective regression of the underlying digit bone. Together, these data show epithelial Wnt ligands can ultimately regulate Wnt signaling in osteoblasts and osteoclast precursors, known to regulate bone homeostasis. These results reveal a critical role for the nail epithelium on the digit bone during homeostatic regeneration and show that Wnt/β-catenin signaling is critical for this interaction.

Are fingernails a key to unlocking the puzzle of mammalian limb regeneration?

“…Collective evidence does demonstrate that Wnt signalling in the broader epithelium supports the surrounding tissues in a pro‐regenerative manner. Deletion of Beta‐catenin in the epithelium perturbs Wnt signalling in the underlying digital bone and affects additional pathways necessary for digit tip regeneration, for example by supporting the proliferation of Runx2+ osteoblasts in the adjacent mesenchyme and subsequent downstream BMP signalling (s12), or by upregulating Sema5a in the epithelium and subsequent FGF signalling ultimately necessary for nerve recruitment and blastema formation (s13,s14) . These data fit nicely with the established necessity for both the nail and Wnt signalling during digit tip regeneration; however, these models are confounded by both scale and precedence.…”

“…demonstrated the necessity of canonical Wnt signalling for nail differentiation via conditional deletion of Beta‐catenin in the epithelium. Moreover, they showed that removal of Beta‐catenin from the epithelium following digit tip amputation not only impairs nail regeneration, but also disrupts regeneration and homoeostasis of the underlying bone . Consistent with this, Lgr6, an agonist of Wnt signalling, has been found to be a marker specific for nail stem cells within the nail matrix, and its activity is ultimately necessary for digit tip regeneration …”

“…While it is conceivable that the concentration, diffusibility or transport of Wnt has been modified specifically in the digit tip to allow for long‐range effect (s20‐s22), it is unlikely that Wnt signalling in the epithelium directly effects signalling throughout the entire digit tip (s23) (Figure ). Instead, Wnt signalling in the nail epithelium likely activates a signalling network in tissues local to the nail, although these secondary signalling pathways would still be subject to the same scaling constraints (s23).…”

Level‐specific amputations and resulting regenerative outcomes in the mouse distal phalanx

“…Previous reports suggest that the nail plate must remain on the digit in order for successful regeneration . More recently, the presence of nail stem cells and activation of canonical Wnt signaling within the proximal nail matrix have been identified as critical regulators of regeneration . Riginelli et al report the regenerative ability of neonatal mouse digits is restricted to levels where the amputation plane is within the Msx1 positive nail bed.…”

Digit Tip Injuries: Current Treatment and Future Regenerative Paradigms

“…Indeed, transplanting the nail bed to the site of a more proximal amputation, which would otherwise undergo fibrotic healing, results in ectopic bone growth as part of a regenerative response [24]. Even in the absence of traumatic injury, epithelium-derived Wnt is necessary for the maintenance of the underlying digit bone, highlighting the importance of this signaling pathway in governing ectodermal-mesodermal interactions in the digit tip [25]. Leucine-rich repeat-containing G protein-coupled receptor 6 (LGR6), a known agonist of the Wnt pathway, has also been identified as a marker for nail stem cells, and its loss prevents a regenerative response [26].…”