Not Just for Patterning Anymore: Hox Genes Function in Skeletal Stem Cells Throughout Life

Hox genes play fundamental and highly conserved roles in vertebrates patterning of the axial and limb skeleton during embryonic development. We have shown that Hox genes continue to be regionally‐expressed through postnatal development and adult life. Hox‐expressing cells are observed only within a subset of the stromal cells defined as progenitor‐enriched mesenchymal stem/stromal cells. Using a Hoxa11‐CreERT2 allele, we show that Hox‐expressing cells lineage label into chondrocytes, osteoblasts, osteocytes and adipose cells at all stages of life, during growth, homeostasis and in response to injury. Further, lineage labeling from any stage, including during embryogenesis, results in the permanent labeling of a self‐renewing skeletal stem cell population, confirming that Hox‐expressing cells are bona fide skeletal stem cells throughout the life of the animal. However, whether Hox genes continue to function after embryonic stages has never been demonstrated. Embryonic patterning roles and perinatal lethality has prevented this question from being addressed. Using our newly generated Hoxd11 conditional allele and temporally restricted deletion only at adult stages, we show that Hox genes continue to play critical roles in skeletal maintenance and repair throughout life. Loss of Hox function leads to dramatic and progressive perturbations in skeletal integrity with loss of collagen organization, and defective osteocyte and osteoblast formation. Loss of Hox function does not lead to loss of the skeletal stem cell population, but rather an inability of early‐stage progenitors to properly differentiate into functional chondrocytes and osteoblasts. How Hox transcription factors direct these differentiation processes throughout the life of the animal is the focus of current investigations.Support or Funding InformationNIH NIAMS R01 AR 061402 and R61 AR073523Hox Skeletal LineageFigure 1