Proteins causing daytime sleepiness tied to bone formation, providing target for osteoporosis

Orexin proteins, which are blamed for spontaneous daytime sleepiness, also play a crucial role in bone formation, according to findings by UT Southwestern Medical Center researchers. The findings could potentially give rise to new treatments for osteoporosis, the researchers say.

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Orexins are a type of protein used by nerve cells to communicate with each other. Since their discovery at UT Southwestern more than 15 years ago, they have been found to regulate a number of behaviors, including arousal, appetite, reward, energy expenditure, and wakefulness. Orexin deficiency, for example, causes narcolepsy – spontaneous daytime sleepiness. Thus, orexin antagonists are promising treatments for insomnia, some of which have been tested in Phase III clinical trials.

UT Southwestern researchers, working with colleagues in Japan, now have found that mice lacking orexins also have very thin and fragile bones that break easily because they have fewer cells called osteoblasts, which are responsible for building bones.

“Osteoporosis is highly prevalent, especially among post-menopausal women. We are hoping that we might be able to take advantage of the already available orexin-targeting small molecules to potentially treat osteoporosis,” said Dr. Yihong Wan, Assistant Professor of Pharmacology, the Virginia Murchison Linthicum Scholar in Medical Research, and senior author for the study, published in the journal Cell Metabolism.

Osteoporosis, the most common type of bone disease in which bones become fragile and susceptible to fracture, affects more than 10 million Americans. The disease, which disproportionately affects seniors and women, leads to more than 1.5 million fractures and some 40,000 deaths annually. In addition, the negative effects impact productivity, mental health, and quality of life. One in five people with hip fractures, for example, end up in nursing homes.

Orexins seem to play a dual role in the process: they both promote and block bone formation. On the bones themselves, orexins interact with another protein, orexin receptor 1 (OX1R), which decreases the levels of the hunger hormone ghrelin. This slows down the production of new osteoblasts and, therefore, blocks bone formation locally. At the same time, orexins interact with orexin receptor 2 (OX2R) in the brain. In this case, the interaction reduces the circulating levels of leptin, a hormone known to decrease bone mass, and thereby promotes bone formation. Therefore, osteoporosis prevention and treatment may be achieved by either inhibiting OX1R or activating OX2R.

“We were very intrigued by this yin-yang-style dual regulation,” said Dr. Wan, a member of the Cecil H. and Ida Green Center for Reproductive Biology Sciences and UT Southwestern’s Harold C. Simmons Comprehensive Cancer Center. “It is remarkable that orexins manage to regulate bone formation by using two different receptors located in two different tissues.”

The central nervous system regulation through OX2R, and therefore promotion of bone formation, was actually dominant over regulation through OX1R. So when the group examined mice lacking both OX1R and OX2R, they had very fragile bones with decreased bone formation. Similarly, when they assessed mice that expressed high levels of orexins, those mice had increased numbers of osteoblasts and enhanced bone formation.

Vera Malheiro - ‘Human osteoblasts in culture’

Microscopy images of human bone cells (osteoblasts) stained with GIEMSA allowing to visualise the cells nucleus, nucleoli and cytoplasm. My PhD project is related to the evaluation of biocompatibility of ferritic stainless steels. In order to perform biocompatibility studies is crucial to understand the types of cells that are used for them. Staining cells allows for the observation of the cell morphology, and this is the most direct technique to identify cell type and screen if there is any problems with them. These particular pictures were taken in the context of a baseline experiment where I was studying the characteristics of foetal human osteoblasts (FHOBS) cells for better comprehension of their biology in vitro. The goal was to access if FHOBS were a valid in vitro model to evaluate the biocompatibility of metallic biomaterials to be used in bone implants. The image has been treated in Photoshop for color change and quality improvement.

Modulation of Selectin-Mediated Adhesion of Flowing Lymphoma and Bone Marrow Cells by Immobilized SDF-1.

Modulation of Selectin-Mediated Adhesion of Flowing Lymphoma and Bone Marrow Cells by Immobilized SDF-1.

Int J Mol Sci. 2014;15(9):15061-15072

Authors: Hedges EA, Hughes AD, Liesveld JL, King MR

Abstract
The α-chemokine, stromal-derived factor-1 (SDF-1), has been linked to the homing of circulating tumor cells to bone. SDF-1 is expressed by bone microvascular cells and osteoblasts and normally functions to attract blood-borne hematopoietic stem and progenitor cells to marrow. It has been shown that treatment of cancer cells with soluble SDF-1 results in a more aggressive phenotype; however, the relevance of the administration of the soluble protein is unclear. As such, a flow device was functionalized with P-selectin and SDF-1 to mimic the bone marrow microvasculature and the initial steps of cell adhesion. The introduction of SDF-1 onto the adhesive surface was found to significantly enhance the adhesion of lymphoma cells, as well as low-density bone marrow cells (LDBMC), both in terms of the number of adherent cells and the strength of cell adhesion. Thus, SDF-1 has a synergistic effect with P-selectin on cancer cell adhesion and may be sufficient to promote preferential metastasis to bone.

PMID: 25167133 [PubMed - as supplied by publisher]



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Picasso Bleeds

You spoke of me with
Rowdin on your tongue,
thinking, thinking, thinking,
chiseling me in the ventricles
of your mind, erecting a
nouveau David that Raphael
would be proud of, reborn as
Venus in the Sistine Chapel,
forgotten in limestone
buried in the Renaissance;
but my bones breathe
melting clocks and starry nights
and atmospheric skulls that feed
calcium to the osteoblasts of
my body’s impression, found in the abandoned quarry of your cerebrum; and I am lost in the descending 
staircase of your friend Duchamp,
praying for the war to end
on the blue canvas of my skin

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