Loss of Notch signaling in skeletal stem cells enhances bone formation with aging.

Skeletal stem and progenitor cells (SSPCs) perform bone maintenance and repair. With age, they produce fewer osteoblasts and more adipocytes leading to a loss of skeletal integrity. The molecular mechanisms that underlie this detrimental transformation are largely unknown.

Hox genes are crucial regulators of periosteal stem cell identity.

Periosteal stem and progenitor cells (PSPCs) are major contributors to bone maintenance and repair. Deciphering the molecular mechanisms that regulate their function is crucial for the successful generation and application of future therapeutics. Here, we pinpoint Hox transcription factors as necessary and sufficient for periosteal stem cell function.

Modulating the systemic and local adaptive immune response after fracture improves bone regeneration during aging.

Tissue injury leads to the well-orchestrated mobilization of systemic and local innate and adaptive immune cells. During aging, immune cell recruitment is dysregulated, resulting in an aberrant inflammatory response that is detrimental for successful healing. Here, we precisely define the systemic and local immune cell response after femur fracture in young and aging mice and identify increased toll-like receptor signaling as a potential culprit for the abnormal immune cell recruitment observed in aging animals.

Rosiglitazone induces adipogenesis of both marrow and periosteum derived mesenchymal stem cells during endochondral fracture healing.

Background: Type 2 diabetes mellitus (T2DM) afflicts about six percent of the global population, and these patients suffer from a two-fold increased fracture risk. Thiazolidinediones (TZDs), including rosiglitazone, are commonly used medications in T2DM because they have a low incidence of monotherapy failure. It is known that rosiglitazone is associated with secondary osteoporosis, further increasing the fracture risk in an already susceptible population.

Systemic NF-κB-mediated inflammation promotes an aging phenotype in skeletal stem/progenitor cells.

Aging tissues undergo a progressive decline in regenerative potential. This decline in regenerative responsiveness has been attributed to changes in tissue-specific stem cells and their niches. In bone, aged skeletal stem/progenitor cell dysfunction is characterized by decreased frequency and impaired osteogenic differentiation potential.

Author Correction: Hox gene expression determines cell fate of adult periosteal stem/progenitor cells.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Propranolol Reverses Impaired Fracture Healing Response Observed With Selective Serotonin Reuptake Inhibitor Treatment.

Selective serotonin reuptake inhibitors (SSRIs) are one of the most commonly prescribed antidepressants worldwide and recent data show significant impairment of fracture healing after treatment with the SSRI fluoxetine in mice. Here, we provide evidence that the negative effects of SSRIs can be overcome by administration of the beta-blocker propranolol at the time of fracture. First, in vitro experiments established that propranolol does not affect osteogenic differentiation.

Hox gene expression determines cell fate of adult periosteal stem/progenitor cells.

Hox genes are evolutionarily conserved transcription factors that during embryonic development function as master regulators of positional identity. In postnatal life, the function of Hox proteins is less clear: Hox genes are expressed during tissue repair, but in this context their function(s) are largely unknown. Here we show that Hox genes are expressed in periosteal stem/progenitor cells in a distribution similar to that during embryonic development.

Age-related inflammation triggers skeletal stem/progenitor cell dysfunction.

Aging is associated with impaired tissue regeneration. Stem cell number and function have been identified as potential culprits. We first demonstrate a direct correlation between stem cell number and time to bone fracture union in a human patient cohort.

Ecto-5'-nucleotidase (CD73) regulates bone formation and remodeling during intramembranous bone repair in aging mice.

Ecto-5'-nucleotidase (CD73) generates adenosine, an osteoblast activator and key regulator of skeletal growth. It is unknown, however, if CD73 regulates osteogenic differentiation during fracture healing in adulthood, and in particular how CD73 activity regulates intramembranous bone repair in the elderly. Monocortical tibial defects were created in 46-52-week-old wild type (WT) and CD73 knock-out mice (CD73) mice.

Mosaic analysis of cell rearrangements during ureteric bud branching in dissociated/reaggregated kidney cultures and in vivo.

Background: Cell rearrangements mediated by GDNF/Ret signaling underlie the formation of the ureteric bud (UB) tip domain during kidney development. Whether FGF signaling also influences these rearrangements is unknown. Chimeric embryos are a powerful tool for examining the genetic controls of cellular behaviors, but generating chimeras by traditional methods is expensive and laborious.

Generation of Nkx2.2:lacZ mice using recombination-mediated cassette exchange technology.

Nkx2.2 encodes a homeodomain transcription factor required for the correct specification and/or differentiation of cells in the pancreas, intestine, and central nervous system (CNS). To follow the fate of cells deleted for Nkx2.