Donald A. Glass

Cbfa1-independent decrease in osteoblast proliferation, osteopenia, and persistent embryonic eye vascularization in mice deficient in Lrp5, a Wnt coreceptor

The low-density lipoprotein receptor–related protein (Lrp)-5 functions as a Wnt coreceptor. Here we show that mice with a targeted disruption of Lrp5 develop a low bone mass phenotype. In vivo and in vitro analyses indicate that this phenotype becomes evident postnatally, and demonstrate that it is secondary to decreased osteoblast proliferation and function in a Cbfa1-independent manner. Lrp5 is expressed in osteoblasts and is required for optimal Wnt signaling in osteoblasts. In addition, Lrp5-deficient mice display persistent embryonic eye vascularization due to a failure of macrophage-induced endothelial cell apoptosis. These results implicate Wnt proteins in the postnatal control of vascular regression and bone formation, two functions affected in many diseases. Moreover, these features recapitulate human osteoporosis-pseudoglioma syndrome, caused by LRP5 inactivation.

WNT7b mediates macrophage-induced programmed cell death in patterning of the vasculature

Macrophages have a critical role in inflammatory and immune responses through their ability to recognize and engulf apoptotic cells. Here we show that macrophages initiate a cell-death programme in target cells by activating the canonical WNT pathway. We show in mice that macrophage WNT7b is a short-range paracrine signal required for WNT-pathway responses and programmed cell death in the vascular endothelial cells of the temporary hyaloid vessels of the developing eye. These findings indicate that macrophages can use WNT ligands to influence cell-fate decisions—including cell death—in adjacent cells, and raise the possibility that they do so in many different cellular contexts.

Molecular bases of the regulation of bone remodeling by the canonical Wnt signaling pathway.

Osteoporosis is a common, prevalent, and debilitating condition, particularly in postmenopausal women. Genetics play a major role in determining peak bone mass and fracture risk, but few genes have been demonstrated conclusively to be involved, much less the signaling pathways with which they are affiliated. The identification of mutations in the gene Lrp5, a Wnt coreceptor, as the cause for both osteoporotic and high-bone mass disorders implicated the canonical Wnt signaling pathway in bone mass regulation. Since Lrp5, other Wnt components have been identified as being regulators of bone mass, and Wnt target genes affecting bone homeostasis have begun to be elucidated. This chapter looks at the various components of the canonical Wnt signaling pathway and the data indicating that this pathway plays a major role in the control of both bone formation and bone resorption, the two key aspects of bone remodeling.

Canonical Wnt signaling in osteoblasts is required for osteoclast differentiation.

Abstract:  Inactivation of Lrp5, a gene encoding a likely Wnt co‐receptor, results in low bone mass (osteopenia) by decreasing bone formation, suggesting that Wnt signaling in osteoblasts regulates bone formation. Here we show that Tcf1 and Tcf4 are expressed in osteoblasts during development and after birth; stabilization of β‐catenin, an essential component of canonical Wnt signaling, in differentiated osteoblasts results in high bone mass while its deletion from differentiated osteoblasts leads to osteopenia. Histological analysis showed that these mutations affect bone resorption. Cellular and molecular studies showed that β‐catenin together with TCF proteins regulates in osteoblasts the expression of Osteoprotegerin, a major inhibitor of osteoclast differentiation. These findings demonstrate that, in differentiated osteoblasts, β‐catenin and presumably Wnt signaling are negative regulators of osteoclast differentiation; thus they broaden our knowledge about functions that Wnt proteins may have at various stages of skeletogenesis.

Poor prognosis in non-Caucasian patients with early-onset mycosis fungoides

BACKGROUND Mycosis fungoides (MF), the most common cutaneous T-cell lymphoma, is most often seen in middle-aged to elderly men. OBJECTIVE We conducted a retrospective study of the demographics and prognosis of patients with onset of MF before age 40 years. METHODS Demographic data (age, sex, and race) and histology from 1074 patents with cutaneous T-cell lymphoma were stratified by age of onset and race and analyzed using Chi-square test. RESULTS Women presented before age 40 years more often than men (P = .038). Early onset of MF was diagnosed in 30 of 92 (32.6%) African American (AA), 31 of 87 (35.6%) Hispanic, and 103 of 809 (12.7%) Caucasian patients. MF was significantly more common in AA (P = .0008) and Hispanic (P = .0002) patients. Early-onset MF was more common among 21 of 60 AA women (35%, P = .0174) and 19 of 40 Hispanic women (47.5%, P = .0002) than among 50 of 350 Caucasian women (14.5%). Progression from initial TNM stage occurred in only 5 (10%) Caucasian, one (5%) Hispanic, and 8 (38%) AA women who presented before age 40 years. Six of 8 AA women who progressed died of their disease whereas two were long-term survivors after allogeneic transplantation. LIMITATIONS This was a retrospective study at one cancer center. CONCLUSION Although MF is considered to be a disease of middle-aged men, early-onset MF is more common among AA and Hispanic women. AA women with early onset may have a poor prognosis and should be considered for more aggressive therapy, including allogeneic transplantation.

Whole exome sequencing.

Our goal is to highlight annually a methodology of significance to the journals domains, either because it has been used clinically or researchwise for our fields of interest or because it holds promise as a tool in diagnosing, treating, or investigating corresponding diseases.We hope another strength of this new section is simplicity of language that can be readily grasped by our readers.

Glutathione Depletion, Pentose Phosphate Pathway Activation, and Hemolysis in Erythrocytes Protecting Cancer Cells from Vitamin C-induced Oxidative Stress

The discovery that oxidized vitamin C, dehydroascorbate (DHA), can induce oxidative stress and cell death in cancer cells has rekindled interest in the use of high dose vitamin C (VC) as a cancer therapy. However, high dose VC has shown limited efficacy in clinical trials, possibly due to the decreased bioavailability of oral VC. Because human erythrocytes express high levels of Glut1, take up DHA, and reduce it to VC, we tested how erythrocytes might impact high dose VC therapies. Cancer cells are protected from VC-mediated cell death when co-cultured with physiologically relevant numbers of erythrocytes. Pharmacological doses of VC induce oxidative stress, GSH depletion, and increased glucose flux through the oxidative pentose phosphate pathway (PPP) in erythrocytes. Incubation of erythrocytes with VC induced hemolysis, which was exacerbated in erythrocytes from glucose-6-phosphate dehydrogenase (G6PD) patients and rescued by antioxidants. Thus, erythrocytes protect cancer cells from VC-induced oxidative stress and undergo hemolysis in vitro, despite activation of the PPP. These results have implications on the use of high dose VC in ongoing clinical trials and highlight the importance of the PPP in the response to oxidative stress.

A Novel Homozygous Missense Mutation in HOXC13 Leads to Autosomal Recessive Pure Hair and Nail Ectodermal Dysplasia

Pure hair and nail ectodermal dysplasia (PHNED) is a rare disorder that presents with hypotrichosis and nail dystrophy while sparing other ectodermal structures such as teeth and sweat glands. We describe a homozygous novel missense mutation in the HOXC13 gene that resulted in autosomal recessive PHNED in a Hispanic child. The mutation c.812A>G (p.Gln271Arg) is located within the DNA‐binding domain of the HOXC13 gene, cosegregates within the family, and is predicted to be maximally damaging. This is the first reported case of a missense HOXC13 mutation resulting in PHNED and the first reported case of PHNED identified in a North American family. Our findings illustrate the critical role of HOXC13 in human hair and nail development.

Current Understanding of the Genetic Causes of Keloid Formation

Keloids are an exuberant response to cutaneous wound healing. Several lines of evidence suggest that keloid scarring is influenced by genetic factors. This review will discuss our current understanding of genetic influences on keloidal scarring via familial inheritance patterns; ethnic differences in prevalence; syndromes with keloid occurrence; linkage analysis, genome-wide association studies, and admixture mapping studies; transforming growth factor beta and p53 variant studies; and human leukocyte antigen polymorphisms.

Association of keloids with systemic medical conditions: a retrospective analysis

Turkish literature, and most of them reported as plant burn. Like other members of the Ranunculaceae family, R. arvensis was used for rheumatic pain in most of these reported patients. However, in our patient, his use for this plant was interesting, because he had used it for treating the pustulas. In the literature, the terms plant burn and phytodermatitis have been frequently used interchangeably. In phytodermatitis, there is an alteration in the anatomic integrity of the skin that may resemble burn injury. As herbal medicine is an easily accessible and affordable treatment, and believed as harmless, many people will continue to use the plants as an alternative treatment. As a result, cases of phytodermatitis seem to become more frequent. Patients should be advised to be careful about the side effects of herbal treatment.