<i>Hox</i> genes maintain critical roles in the adult skeleton.

Abstract

<i>Hox</i> genes are indispensable for the proper patterning of the skeletal morphology of the axial and appendicular skeleton during embryonic development. Recently, it has been demonstrated that <i>Hox</i> expression continues from embryonic stages through postnatal and adult stages exclusively in a skeletal stem cell population. However, whether <i>Hox</i> genes continue to function after development has not been rigorously investigated. We generated a <i>Hoxd11</i> conditional allele and induced genetic deletion at adult stages to show that <i>Hox11</i> genes play critical roles in skeletal homeostasis of the forelimb zeugopod (radius and ulna). Conditional loss of <i>Hox11</i> function at adult stages leads to replacement of normal lamellar bone with an abnormal woven bone-like matrix of highly disorganized collagen fibers. Examining the lineage from the <i>Hox-</i>expressing mutant cells demonstrates no loss of stem cell population. Differentiation in the osteoblast lineage initiates with Runx2 expression, which is observed similarly in mutants and controls. With loss of Hox11 function, however, osteoblasts fail to mature, with no progression to osteopontin or osteocalcin expression. Osteocyte-like cells become embedded within the abnormal bony matrix, but they completely lack dendrites, as well as the characteristic lacuno-canalicular network, and do not express SOST. Together, our studies show that <i>Hox11</i> genes continuously function in the adult skeleton in a region-specific manner by regulating differentiation of <i>Hox</i>-expressing skeletal stem cells into the osteolineage.