Jarcome-Galarza et al. J Bone Miner Res.
It is known that the bone marrow contains three main types of stem cells: a) hematopoietic stem cells, which make blood; b) endothelial progenitor cells, which maintain healthy blood vessels; and c) mesenchymal stem cells, which repair a variety of tissues and are capable of producing high amounts of growth factors. After major tissue injury or trauma all three of the bone marrow derived stem cells leave the bone marrow and enter systemic circulation in an attempt to heal the tissue damage. The original compound that was discovered to “mobilize” bone marrow stem cells was granulocyte colony stimulating factor (G-CSF). Studies in mice with lung injury in the late 1970s demonstrated that a lung-derived protein was capable of stimulating bone marrow to multiply and produce higher numbers of granulocytes. It was not until the late 1980s that scientists started injecting purified G-CSF into animals as a method of increasing the number of circulating stem cells. Why would people want to increase circulating stem cells? Commercially one of the main reasons is associated with the process of bone marrow transplantation. In bone marrow transplantation donors were historically required to undergo the painful procedure of bone marrow extraction, which requires an excess of 20 holes to be drilled into their hip bones. Compounds such as G-CSF could be administered to donors in order to make their stem cells enter circulation, and then the stem cells could be isolated from the blood instead of the bone marrow. This makes the procedure a lot less painful and arguably a lot safer. Additionally, the possibility of mobilizing stem cells by administration of a drug has the possibility of artificially increasing stem cell numbers in patients with degenerative diseases in order to attempt to naturally heal the condition.
The clinical use of G-CSF for mobilization and also for increasing granulocytes in the blood has resulted in multibillion dollars per year in sales for companies such as Amgen. Naturally, this has stimulated much interest in the process of how to make stem cells leave the bone marrow. G-CSF stimulates bone marrow stem cell release through several mechanisms. The main mechanism appears to be associated with stimulation of osteoclasts, which cause modulation of the bone marrow structure and physically release the stem cells from their environment. Other mechanisms exist such as breakdown of stromal derived growth factor (SDF-1). This protein is made by the bone marrow and literally keeps the hematopoietic stem cells stuck to the bone. When the bone marrow levels of SDF-1 decrease, the hematopoietic stem cells are no longer “stuck” to the marrow and as a result enter circulation. Yet another mechanism is that G-CSF activates neutrophils to produce various enzymes that cleave proteins on the bone marrow. These cleaved proteins are then recognized by pre-formed antibodies, which activate complement, which causes small holes in the bone marrow and thus releases stem cells.
The second “stem cell mobilizer” to be approved by the FDA is a drug called Mozibil which blocks the interaction between SDF-1 and its receptor CXCR4. This drug was sold by Anormed to Genzyme in a deal worth more than half a billion dollars. Mozibil is a superior stem cell mobilizer to G-CSF in many patients and as a result has rapidly been implemented clinically. Interestingly, it appears that Mozibil causes redistribution of different ratios of hematopoietic, mesenchymal and endothelial progenitor cells than G-CSF.
One of the most recent mobilizers under development is Parathyroid Hormone. This naturally –occurring substance has been demonstrated in clinical trials to mobilize stem cells, but apparently through a mechanism different than G-CSF and Mozibil. Specifically, both of these drugs appear to cause a temporary depletion of the stem cells in the bone marrow, whereas Parathyroid Hormone seems to preserve the stem cells inside of the bone marrow.
A recent paper (Jacome-Galarza et al. Parathyroid hormone regulates the distribution and osteoclastogenic potential of hematopoietic progenitors in the bone marrow. J Bone Miner Res. 2010 Dec 29) explored the activities of Parathyroid Hormone on osteoclasts in the bone marrow of mice. The authors found that treatment of mice with Parathyroid Hormone for 7 or 14 days increased the number of osteoclastic progenitors in the bone marrow as well as the absolute number of hematopoietic progenitors. These data suggest that the hormone acts not only as a means of stimulating redistribution of hematopoietic stem cells, but also may be involved in directly stimulating their multiplication, possibly through modulating activity of osteoclasts.
