Fw: Blood vessels found to signal chain of destruction in bone diseases

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From: " ilena rose " <ilena@...>

Sent: Tuesday, June 26, 2001 7:51 PM

Subject: Blood vessels found to signal chain of destruction in bone diseases

> Blood vessels found to signal chain of destruction in bone diseases

>

> Biologists at Washington University in St. Louis have discovered a

> mechanism in blood vessels that opens the door for bone loss in such

> diseases as rheumatoid arthritis, periodontal disease, osteoporosis,

> tumor-associated bone loss, or artificial implant loosening.

>

> Collin-Osdoby, Ph.D., research associate professor of biology in

> Arts & Sciences at Washington University, and Philip Osdoby, Ph.D.,

> professor of biology in Arts & Sciences, and Rothe, Washington

> University research associate, have for the first time shown that blood

> vessels at inflamed sites where bone loss is occurring create signals that

> set into motion a cascade of events leading to local bone destruction.

>

> When an area of tissue in or near bone becomes inflamed, key molecules

> called cytokines are locally produced and increase in the bloodstream.

> Studying human tissue and cell samples, the Osdobys have shown that two

key

> inflammatory cytokines, interleukin-1 (IL-1) and tumor necrosis factor

> (TNF), signal the endothelial cells of blood vessels and capillaries to

> make and display on their cell surface a molecule called RANKL. RANKL is

> the critical signal that tells the body to make and activate

bone-degrading

> cells called osteoclasts. After osteoclasts take bone away, osteoblasts go

> back in and add new bone. Normally, this bone remodeling, which is

> associated with a blood vessel or capillary at such sites, is a carefully

> balanced process. However, in persons with inflammatory bone disease,

> osteoclasts out-number and out-work the bone-forming osteoblasts, leading

> to weakened bone matrix, bone loss, and an increased risk of fracture. The

> Osdobys believe that inflamed blood vessels beckon cells to the region,

and

> then initiate their development into highly active bone-degrading

> osteoclasts.

>

> The researchers also found that in this biochemical chain of events, the

> blood vessels themselves make an antagonist molecule, osteoprotegerin

> (OPG), which neutralizes RANKL activity. Although OPG is made in this

> process, it peaks early and RANKL gets the upper hand. This is aided by

the

> fact that RANKL is tethered on the cell surface while OPG is a soluble

> molecule that can be carried away by the circulation.

>

> Drug chemical companies are interested in RANKL as a target and OPG as a

> possible therapeutic or preventative molecule to eliminate excessive

> osteoclast formation and activity. It is the progressive and irreversible

> loss of bone and cartilage that is the most difficult to control and treat

> in rheumatoid arthritis, periodontal disease or cancer. Current

> anti-inflammatory or chemotherapeutic treatments are inadequate for this

> purpose. However, OPG injection prevents such bone and cartilage loss,

> without interfering with normal bone remodeling.

>

> More significantly, the discovery that blood vessel cells themselves are

> initiators of this elaborate process could make drug delivery easier or

> more efficient. Rather than receiving a local injection, patients may be

> able to take an oral or systemic dose that goes directly into the blood

> stream and allows the drug to work immediately in the early stages of

RANKL

> activity. This could prevent new areas of bone degradation from getting

> started and slow down those that have already begun.

>

> " People in the past few years have been looking at the expression of RANKL

> and OPG in bone marrow stromal cells, osteoblasts and T cells, but nobody

> had looked in blood vessels, " Collin-Osdoby said. " There is a growing

> appreciation that blood vessels do much more in the body than simply

> provide a physical barrier and a route to passively deliver nutrients and

> cells. Our findings show that blood vessels can play a key role in

actively

> regulating bone remodeling and physiology. "

>

> According to Osdoby, the discovery opens up several options to eliminate

or

> minimize bone loss in inflammatory-related diseases.

>

> " Because we know that blood vessels overgrow and are activated to cause

> osteoclast formation in inflammatory disorders, researchers can begin to

> think of ways to dampen the formation of new blood vessels or capillaries,

> deactivate the osteoclasts, or neutralize the RANKL expressed, " he said.

> " It's the osteoclasts that are directly responsible for the loss of bone,

> even though many other cell types, signals, and enzyme activities are

> produced and play a role. So, the most obvious approach to prevent such

> bone loss is to directly interfere with the formation of bone-degrading

> osteoclasts. "

>

> The research was published in the June, 2001 issue of the Journal of

> Biological Chemistry. The research was supported by the National

Institutes

> of Health.

>

> Such popular arthritis drugs as Vioxx, Celebrex, and Enbrel work on the

> principal of interrupting the work of the cytokines to ease inflammation.

> Vioxx and Celebrex interrupt a similar cascade of events by preventing

IL-1

> from generating prostaglandins at inflammatory sites. Enbrel suppresses

the

> work of TNF. However, something more is needed to avoid bone and cartilage

> destruction. Collin-Osdoby said that the balance between the levels of

> RANKL and OPG produced is critical for determining the amount of

osteoclast

> formation and bone breakdown that occurs. Previous studies have shown that

> the absence of RANKL in mice leads to too much bone formation

> (osteopetrosis) because osteoclasts are not formed, whereas the absence of

> OPG in mice leads to severe bone loss and osteoporosis. Interestingly,

mice

> lacking the OPG gene also have calcified arteries, leading to diseased

> blood vessels.

>

> " We've shown that the endothelial cells of blood vessels make their own

OPG

> and may represent a major source for the levels of this factor found

> circulating in serum, " she said. " In the case we've studied, the amount of

> OPG that endothelial cells make is regulated by inflammatory cytokines. "

>

> The finding that RANKL and OPG are produced by vascular endothelial cells

> also has broader implications for the role of blood vessels in organ

> development and immune regulation. This is because RANKL also is critical

> for the formation of lymph nodes, lymphocytes, and immune cell

> interactions, while OPG counteracts cell death signals (by TRAIL

molecules)

> to which cancer cells are particularly sensitive.

>

> In addition to further RANKL studies, the Osdobys also will be looking

> closely at OPG production in response to key regulators of endothelial

> cells because this molecule seems to provide some survival benefits for

the

> endothelial cells themselves.