'Gonna Roll The Bones' - Bones Key to Blood; Implications for Transplants

[Guest guest]

Bones hold the key to blood renewal

Though we think of them as solid and permanent, our bones are

actually constantly being rebuilt throughout our lives. A team of

scientists at the Weizmann Institute of Science has now revealed how

cells that work at remodeling the bones play a direct part in the

ongoing renewal of another system – the blood. Their findings, which

may lead to future improvements in bone marrow transplantation and a

better understanding of diseases involving bone or blood renewal,

were published in the June issue of Nature Medicine.

Bones are really two systems in one. The cavities inside bones are

filled with spongy bone marrow, in which stem cells divide and their

daughter cells differentiate into all kinds of blood cells, including

large numbers of immune cells for the body's defense. The

hematopoietic (literally, blood-creating) stem cells, which can give

rise to any kind of blood cell, reside in special 'stem cell niches'

nestled in the bones' inner walls. Inside these sheltered nurseries,

the stem cells remain undifferentiated; with the help of other nearby

cells, they hang on to their juvenile qualities. Only when they leave

the niches do they morph into specialized blood cells, possibly

becoming immune cells for fighting infection or cells for blood

clotting and healing after injury. They can even respond to calls for

help from organs such as the liver, migrating through the bloodstream

to assist in repairing damage.

The inner walls of the bones are also sites of intensive

reconstruction. While one type of cell, the osteoblast, is busy

building bone, its partner, the osteoclast, breaks it down and

reassimilates the material. Osteoclasts are formed when several cells

(which themselves originate from hematopoietic stem cells) fuse

together at a signal from the osteoblasts, and the two work together

in a sort of 'urban renewal' scheme to keep the bones healthy and

strong.

The Weizmann Institute team headed by Prof. Tsvee Lapidot of the

Immunology Department, which included Dr. Orit Kollet and colleagues,

found that the bone-dismantling osteoclasts are instrumental in

releasing hematopoietic stem cells into the bloodstream. As they wear

away the bone, they allow the stem cells out of the niches and into

the bloodstream. Although some hematopoietic stem cells can always be

found circulating in the blood, when there is bleeding or

inflammation in the body, more stem cells are needed to deal with the

situation and restore balance. The team's study showed that the bone

marrow response to the body's call for help involves stepping up

production of osteoclasts, putting machinery that normally operates

at a leisurely pace into high gear. The osteoclasts not only clear

away bone, they also break up 'nurturing' substances in the niche

that attract and hold the stem cells to that spot, thus allowing more

stem cells into the bloodstream.

The team carried out their research on mice, including some developed

in the lab of Prof. Ari Elson of the Molecular Genetics Department,

in which the osteoclasts carried a mutation that rendered them only

partially functional in the young females. They found abnormally low

stem cell levels in the blood of these mice even when they tried to

encourage their mobilization, giving them solid evidence of the

connection. In normal mice, using a chemical compound that stimulates

osteoclast formation, they were able to boost osteoclast levels and

thus manage the release of stem cells into the blood in a variety of

stress situations.

This finding may have implications for bone marrow transplant

techniques: The drugs given today to donors to increase the supply of

stem cells in their bloodstream before they are harvested for

transplantation cause the release of many other mature cells as well.

Injecting the osteoclast-promoting substance into the mice, on the

other hand, resulted in an increase mainly in stem cell release.

These findings add a new dimension to our understanding of the

processes of renewal and breakdown in the body, and the relationship

between blood-forming stem cells, bone, and the immune system. In

some forms of osteoporosis, autoimmune arthritis, and cancer that has

metastasized to the bone, for instance, the osteoclasts demolish bone

faster than it is built up. This study suggests the effects of such

an imbalance may reach well beyond the bone.

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BTW, 'Gonna Roll The Bones' is the title of a great science fiction

short story by Fritz Leiber that won the Hugo and Nebula Awards in

1968.