Vascular Biology and the Skeleton

Abstract

BLOOD VESSELS ARE organized in a hierarchical fashion to deliver oxygen, soluble factors, and various types of cells to all tissues in our body in a carefully regulated manner. The vascular network forms by both vasculogenesis (de novo vessel formation from angioblastic stem cells) and angiogenesis (sprouting from existing vessels). (1-3) Both processes are essential during skeletal embryogenesis or repair, but otherwise represent pathological events linked to adverse consequences. The endothelium is one of the most important components of the vasculature, not only because it functions as an essential barrier that limits the movement of cells and molecules between the circulation and tissues, but also because it is a dynamic organ actively capable of directly communicating in a rich language with adjacent tissue and circulating blood cells. This appears evident when considering the remarkable heterogeneity of endothelial cells and their vessel size-specific, tissue-specific, and age-specific differences. (4, 5) What is the underlying cause of endothelial diversity? Certainly during development and ongoing tissue maintenance in the adult, circulatory and tissue components must continually communicate with endothelial cells. (5) However, the signaling between cells and endothelium within a tissue is, in fact, bidirectional, and endothelial cells just as readily communicate with surrounding cells through a host of humoral and growth factors, cytokines and chemokines, reactive metabolites, and polarized surface-associated molecules. (5) Vasculature plays a major role also in the fabrication and homeostatic "health" of living bone, without which bone tissue dies and cannot be repaired or rejuvenated. (6, 7) The development of various "in vitro" models of bone endothelial cells has helped us to gain a better understanding of why the vasculature is so important in bone, what unique features characterize the bone endothelium, and how it functionally interacts with bone cells of different nature. (8-24) In particular, bone endothelium has been found to actively recruit circulating cells, direct hematopoietic cell homing to the bone marrow, and collaborate with various metastatic cells to selectively target them into bone, largely through the preferential display on bone endothelium of particular attractant signals that orchestrate such movement. (19, 20, 25-30) In addition, modifications in the blood supply correlate with numerous skeletal pathologies, including osteoporosis or osteopetrosis, inflammatory bone loss, and tumor-associated osteolysis. (31-33) This overview is intended to highlight the potential roles of various paracrine interactions between bone endothelium and differentiated bone cells during organogenesis or in the mature skeleton, with brief consideration given to bone vascularization in pathological conditions. Potential implications of this growing body of information for medicine are noted. The vasculature in bone is important for skeletal development and growth by affecting both bone modeling and remodeling processes. The majority of bones in the vertebrate skeleton are formed by endochondral ossification, a process initiated in the embryo by mesenchymal condensation, that gives rise to cartilage elements which, in turn, are invaded by blood vessels that bring along perivascular osteoprogenitor cells and recruit osteoclasts, leading to these elements being resorbed and gradually replaced by bone tissue. (34-36) The developmental pattern of the vascular network is an important component coordinating or directing limb morphogenesis. (37) Early in osteogenesis, the cartilage appears to produce anti-angiogenic factors that inhibit vessel penetration. (38-45) However, vascularization is required for osteogenesis to occur, and this is accomplished by a combination of factors, including adequate oxygen tension, compression forces, nutrients, and growth and differentiative factors. During or after vascular invasion, the hypertrophied cartilage core is degraded by chondroclasts/osteoclasts and replaced by bone marrow and later by bone initially deposited on calcified cartilage spicules. The vasculature may direct such new bone formation by serving as a scaffolding for bone-forming cells. Indeed, the intimacy of endothelial cells and osteoblasts has led in the past to the theory that the endothelial cell itself is an osteoblast precursor. (46) More recently, it has been proposed that bone marrow stromal cells (which are known to be capable of differentiating into osteoblasts) are actually a bone-specific type of microvascular pericyte, cells that are tightly affiliated with capillary endothelial cells and exhibit multilineage (osteogenic, chondrogenic, adipogenic, and fibroblastic) potential. (47-52) Thus, pericytes may be supplied by the invading vasculature and constitute a cellular reserve for use in bone tissue formation, remodeling, or repair. (47) Consistent with this, only cells that are situated