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Bone consists of separate inner endosteal and outer periosteal compartments, each with distinct contributions to bone physiology and each maintaining separate pools of cells owing to physical separation by the bone cortex. The skeletal stem cell that gives rise to endosteal osteoblasts has been extensively studied; however, the identity of periosteal stem cells remains unclear 1 – 5 . Here we identify a periosteal stem cell (PSC) that is present in the long bones and calvarium of mice, displays clonal multipotency and self-renewal, and sits at the apex of a differentiation hierarchy. Single-cell and bulk transcriptional profiling show that PSCs display transcriptional signatures that are distinct from those of other skeletal stem cells and mature mesenchymal cells. Whereas other skeletal stem cells form bone via an initial cartilage template using the endochondral pathway 4 , PSCs form bone via a direct intramembranous route, providing a cellular basis for the divergence between intramembranous versus endochondral developmental pathways. However, there is plasticity in this division, as PSCs acquire endochondral bone formation capacity in response to injury. Genetic blockade of the ability of PSCs to give rise to bone-forming osteoblasts results in selective impairments in cortical bone architecture and defects in fracture healing. A cell analogous to mouse PSCs is present in the human periosteum, raising the possibility that PSCs are attractive targets for drug and cellular therapy for skeletal disorders. The identification of PSCs provides evidence that bone contains multiple pools of stem cells, each with distinct physiologic functions. A periosteal stem cell specialized in intramembranous bone formation has been identified and was found to be essential for normal bone development and fracture healing.

Hedgehog signaling is essential for bone formation, including functioning as a means for the growth plate to drive skeletal mineralization. However, the mechanisms regulating hedgehog signaling specifically in bone-forming osteoblasts are largely unknown. Here, we identified SLIT and NTRK-like protein-5( Slitrk5 ), a transmembrane protein with few identified functions, as a negative regulator of hedgehog signaling in osteoblasts. Slitrk5 is selectively expressed in osteoblasts and loss of Slitrk5 enhanced osteoblast differentiation in vitro and in vivo. Loss of SLITRK5 in vitro leads to increased hedgehog signaling and overexpression of SLITRK5 in osteoblasts inhibits the induction of targets downstream of hedgehog signaling. Mechanistically, SLITRK5 binds to hedgehog ligands via its extracellular domain and interacts with PTCH1 via its intracellular domain. SLITRK5 is present in the primary cilium, and loss of SLITRK5 enhances SMO ciliary enrichment upon SHH stimulation. Thus, SLITRK5 is a negative regulator of hedgehog signaling in osteoblasts that may be attractive as a therapeutic target to enhance bone formation. Hedgehog signaling is essential for bone formation. Here, the authors show that the transmembrane protein SLITRK5 is a negative regulator of hedgehog signaling in osteoblasts, suggesting it may be a potential therapeutic target to enhance bone formation.

Neurofibromatosis type I (NF1) is characterized by prominent skeletal manifestations caused by NF1 loss. While inhibitors of the ERK activating kinases MEK1/2 are promising as a means to treat NF1, the broad blockade of the ERK pathway produced by this strategy is potentially associated with therapy limiting toxicities. Here, we have sought targets offering a more narrow inhibition of ERK activation downstream of NF1 loss in the skeleton, finding that MEKK2 is a novel component of a noncanonical ERK pathway in osteoblasts that mediates aberrant ERK activation after NF1 loss. Accordingly, despite mice with conditional deletion of Nf1 in mature osteoblasts ( Nf1 fl/fl ;Dmp1-Cre ) and Mekk2 −/− each displaying skeletal defects, Nf1 fl/fl ;Mekk2 −/− ;Dmp1-Cre mice show an amelioration of NF1-associated phenotypes. We also provide proof-of-principle that FDA-approved inhibitors with activity against MEKK2 can ameliorate NF1 skeletal pathology. Thus, MEKK2 functions as a MAP3K in the ERK pathway in osteoblasts, offering a potential new therapeutic strategy for the treatment of NF1. Neurofibromatosis type I (NF1) is characterized by prominent skeletal abnormalities mediated in part by aberrant ERK pathway activation due to NF1 loss-of-function. Here, the authors report the MEKK2 is a key mediator of this aberrant ERK activation and that MEKK2 inhibitors, including ponatinib, ameliorate skeletal defects in a mouse model of NF1.

To determine the maximum tolerated dose and dose-limiting toxicity (DLT) of the novel anticancer agent, motexafin gadolinium (MGd), administered concurrently with radiation therapy (RT) in patients with locally advanced pancreatic or biliary tumors. The pharmacokinetics of MGd were also evaluated. Cohorts of three to six patients were treated with escalating doses of MGd, administered three times per week for a total of 16 doses concurrent with RT. The dose of RT was fixed at 5,040 cGy, and given in 28 fractions, from Monday to Friday of every week. Plasma MGd concentrations were measured by high performance liquid chromatography. Eight patients were treated at dose level 1 (2.9 mg/kg), with one DLT (grade 3 fever). Three patients were treated at dose level 2 (3.6 mg/kg), and two DLTs were noted. One DLT was grade 3 nausea and vomiting (N/V), and the other was grade 3 skin toxicity. The most common toxicity was N/V. There were no objective responses. The median survival was 6 months. The MGd plasma concentration versus time profile in each patient was best fit by a two-compartment, open, linear model. There was minimal accumulation of MGd in plasma with the three-times/week dosing schedule. Simulation of the time course of MGd in the peripheral compartment indicated that maximal MGd concentrations of 1-2 micromol/kg occurred between 4 and 6 h after MGd infusion. Dose level 1 (2.9 mg/kg of MGd) is the recommended dose for combination with (RT) in phase II studies for locally advanced pancreatic and biliary cancers. Patient tolerance might be improved by modification of the RT schedule and antiemetic prophylaxis.

Victims of a radiation terrorist event will include pregnant women and unborn fetuses. Mitochondrial dysfunction and oxidative stress are key pathogenic factors of fetal irradiation injury. The goal of this preclinical study is to investigate the efficacy of mitigating fetal irradiation injury by maternal administration of the mitochondrial-targeted gramicidin S (GS)- nitroxide radiation mitigator, JP4-039. Pregnant female C57BL/6NTac mice received 3 Gy total body ionizing irradiation (TBI) at mid-gestation embryonic day 13.5 (E13.5). Using novel time- and-motion-resolved 4D magnetic resonance imaging (4D-uMRI), we found TBI caused extensive injury to the fetal brain that included cerebral hemorrhage, loss of cerebral tissue, and hydrocephalus with excessive accumulation of cerebrospinal fluid (CSF). Histopathology of the fetal mouse brain showed broken cerebral vessels and elevated apoptosis. Further use of novel 4D Oxy-wavelet MRI capable of probing mitochondrial function in intact brain revealed significant reduction of mitochondrial function in the fetal brain after 3Gy TBI. This was validated by Oroboros mitochondrial respirometry. Maternal administration JP4-039 one day after TBI (E14.5), which can pass through the placental barrier, significantly reduced fetal brain radiation injury and improved fetal brain mitochondrial respiration. This also preserved cerebral brain tissue integrity and reduced cerebral hemorrhage and cell death. As JP4-039 administration did not change litter sizes or fetus viability, together these findings indicate JP4-039 can be deployed as a safe and effective mitigator of fetal radiation injury from mid-gestational in utero ionizing radiation exposure. Mitochondrial-targeted gramicidin S (GS)-nitroxide JP4-039 is safe and effective radiation mitigator for mid-gestational fetal irradiation injury.