Bone is a highly vascular organ. It has been known for many years that endochondral bone development coincides with angiogenesis in bone (1). However, the molecular signals that regulate the development of bone and its vascular system and the importance of their interactions for bone development has only recently been appreciated. It is now recognized that bone cells make factors that regulate angiogenesis. Among these, vascular endothelial growth factor (VEGF), a major stimulus of angiogenesis, plays an important role. Additional studies have shown that production of VEGF in a variety of tissues, including bone cells, is regulated by a family of transcription factors termed hypoxia-inducing factors (HIF) (2). These heterodimeric proteins are composed of alpha and beta subunits. There are three HIF alpha subunits whose protein levels in cells are regulated by the oxygen tension in that cell. Perhaps the most studied is HIF1α. Previous work demonstrated that targeted overexpression of HIF1α in the osteoblasts of mice increased their bone mass (3). Conversely, deletion of HIF1α in osteoblasts decreased bone mass (3). Hence, HIF1α production in osteoblasts appears necessary for normal bone development and growth. In addition, it was shown that estrogen destabilized HIF1α protein in osteoclasts and, in this way, prevented osteoclast activation and bone loss (4). In mice with a targeted deletion of HIF1α in osteoclasts, estrogen withdrawal after ovariectomy (a model of the post-menopausal state) did not cause bone loss as it did in normal mice.
Now two papers from the laboratory of Ralf Adams (5, 6) have examined the role that endothelial cells, which line blood vessels, play in bone development. These authors identified specialized endothelial cells in the metaphysis of mouse bones, which they termed H to distinguish them from endothelial cells in the diaphysis, which they term L. H endothelium was relatively unique to metaphsyl bone and could only be found in one other organ, the liver. Furthermore, osteoprogenitor cells, which form osteoblasts and osteocytes, uniquely clustered around type H but not type L endothelial cells. Most fascinating, aging was associated with a decreased numbers of type H but not type L endothelium in bone. This group then examined whether production of HIF1α in endothelial cells regulated the development of type H endothelium and bone mass. Using targeted deletion and targeted enhanced expression of HIF1α in the endothelial cells of mice, they demonstrated that deletion of HIF1α markedly decreased H type endothelium and bone mass without affecting L cells. Conversely, enhanced expression of HIF1α in endothelium increased H cells and bone mass. This group also identified notch signaling in endothelial cells and noggin production by these cells as being involved in the coupling of endothelial cells with osteoprogenitor cells. Significantly, these authors showed that treatment of mice with the iron-chelating drug, deferoxamine mesylate, which inhibits HIF1α degradation and increases intracellular HIF1α protein levels in cells, caused both H type cells in the metaphysis and bone mass to increase in mice. Similarly, Liu et al (7) found that treatment of mice with drugs, which increase HIF1α levels, increase bone mass in ovariectomized mice and Wan et al (8) showed that analogous therapy enhanced bone regeneration in a distraction gap model in mice.
Overall, these studies add much to our understanding of the interaction of bone with its blood vessels. There is some contradiction in the mouse data, which needs to be resolved, since Miyauchi et al (4) found that inhibiting HIF1α selectively in osteoclasts prevented ovariectomy-induced bone loss while Liu et al (7) found that globally enhancing HIF1α with drugs increased bone mass in this condition. Iron-chelating drugs are already approved to treat humans with conditions associated with iron overload. Most exciting is the prospect that these or other agents, which globally increase HIF1α levels in cells, may have utility as agents to treat osteoporosis and other diseases associated with a relative decrease in osteoblast activity.
Farmington, CT, USA
The Interactions of Bone with Its Vascular System
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