The work by Hauge et al. [40
] demonstrated that the cells in the BMU, even in cancellous bone, were not directly contiguous to the bone marrow, but rather they were covered by a “canopy” of cells forming the outer lining of a specialized vascular structure with the denuded bone surface as the other delineation. The cells of this canopy display all classicial markers of the osteoblastic phenotype (Table ), and are therefore most probably bone-lining cells, which seem to be connected to bone-lining cells on the quiescent bone surface. The structure has been demonstrated in cortical as well as cortical bone (Fig. ). In turn, these bone-lining cells on the quiescent bone surface are in communication with osteocytes embedded within the bone matrix. Penetrating the canopy of bone-lining cells, and presumably serving as a conduit for the cells needed in the BMU, are capillaries.
Osteoblastic and endothelial markers detected on cells lining the Bone remodeling Compartment (BRC) vs. vascular endothelial cells as assessed by immuno- and enzyme histochemical staining
Fig. 2 Different representations of BRC structures in cortical (upper panel) and trabecular bone (lower panel). In cortical bone the BRC (outer demarcation by the broken line) is filled with erythrocyte ghosts (EG) and is located at the closing cone of the Haversian (more ...)
Angiogenesis is closely associated with bone resorption and bone and angiogenic factors like VEGF and endothelin regulate osteoclast and osteoblast activity [41
]. In addition blood vessels serve as a way of transporting circulating osteoblast [42
] and osteoclast precursors [43
] to sites undergoing active remodeling. The involvement of vascular cells during the initiation of bone resorption is still unresolved. Is the very first step adhesion of a blood vessel to bone lining cells at a site where targeted repair is needed? Conceivably, osteocyte apoptosis and possible release of osteotropic growth factors and cytokines could be attractants for blood vessels, which would then subsequently initiate the formation of a resorptive BRC. But, as outlined above, the framework for signaling within the osteocyte-lining cell-BRC network could also be a way by which remodeling events on bony surfaces are triggered from damage accumulation or changes in mechanical strain within bone.
There is increasing evidence for a common lineage and close interaction between vascular endothelial cells and bone cells. Endothelial cells drive differentiation of marrow stromal cell towards the osteoblastic phenotype [44
] Endothelin and VEGF are also involved in signaling between vasculature and bone [45
], and VEGF as well as other angiogenic factors are expressed during intramembranous osteogenesis. Osteoblastic cells, as well as osteoclasts, possess receptors for VEGF and also produce VEGF [46
]. Expression of VEGF is closely associated with the early phases of bone modeling and remodeling events [47
] and it induces osteoblast chemotaxis and differentiation [48
] and differentiation.
Cells may enter the remodeling space either via diapedesis through the lining cell dome covering the BRC or via the circulation. It is still debatable whether all cells involved in remodeling arrive via the circulation, but while circulating osteoclast precursors were demonstrated more than a decade ago, there is now increasing evidence that osteoblast lineage cells are also present in the circulation strengthening the involvement of circulating precursor cells in the process [42
While the systemic hormonal regulation of the remodeling process has to occur via factors arriving at individual remodeling sites via the bloodstream, the way by which local regulatory factors exert their action on individual cell populations involved is still obscure. Over the last decades, however, we have increased our knowledge about the different growth factors and cytokines involved in local regulation of bone remodeling tremendously (Fig. ). Apart from growth factors and cytokines, simple molecules like nitrogen oxide (NO), as well as hypoxia and acidosis have been shown to exert pronounced effects on bone remodeling balance and activity. NO exerts biphasic effects on osteoclast activity with low concentrations potentiating and high concentrations inhibiting bone resorption [51
]. Similarly, osteoblastic growth and differentiation are inhibited by high concentrations of NO, while lower concentrations may play a role in regulating normal osteoblast growth and in mediating the effects of estrogens on bone formation, mechanotransduction and bone anabolic responses [51
]. The dominating isoform of nitrogen oxide synthase (eNOS) is expressed in osteocytes and lining cells, but not in cuboidal osteoblasts [52
]. Acidosis and hypoxia generally increase bone resorption [53
] and inhibit bone formation [57
]. As hypoxia may cause acidosis through increased anaerobic metabolism, the two factors may act synergistically at the tissue level [56
]. Hypoxia and acidosis also affect secretion of pro-angiogenic factors like VEGF as outlined below.
Fig. 3 Depiction of some of the main local regulatory factors operating at remodeling sites with osteoclasts (OC) and osteoblasts (OB). Interleukins (IL), tumor necrosis factors (TNF), transforming growth factors (TGF), colony stimulating factors (CSF), Insulin (more ...)