The Bone Remodeling Compartment: A Circulatory Function for Bone Lining Cells

Abstract

ILIAC BONE histomorphometry has from its beginning been plagued by technical problems. To preserve the discrimination between mineralized bone and osteoid and the fixation of tetracycline, sections must be cut without decalcification, which needs plastic embedding and special microtomes. The boundary between hard brittle bone and soft friable marrow has been especially contentious—general acceptance that most of this boundary is occupied by bone lining cells took many years, and there is still disagreement about whether an additional layer of cells invests the marrow.1 One of the pioneers of bone histomorphometry was Philippe Bordier, who died prematurely in 1977. His collaboration with Howard Rasmussen led to an unusual book2; its central theme was borrowed from Harold Frost,3 but it presented many novel observations and penetrating insights. One such observation was that bone lining cells (which they referred to as “mesenchymal cells”) persist as a canopy over sites of remodeling, separating both osteoclasts and osteoblasts from the marrow. This notion has always appealed to me, although it was generally ignored and only rarely was I convinced that I could see the canopy in sections from my own laboratory. Rasmussen and Bordier believed that the location of osteoclasts and osteoblasts beneath the canopy was a consequence of their origin from lining cells, but this is definitely wrong for osteoclasts,4 although it could still sometimes be true for osteoblasts.5 If, as is commonly assumed, osteoclasts arise from precursors in the adjacent hematopoietic marrow that wander directly to the bone surface, they would somehow have to burrow underneath the lining cells. Hauge et al.6 have now convincingly rediscovered the canopy and presented evidence that it provides a conduit for osteoclast precursors. Thus, these cells reach the bone surface via the circulation, not only in cortical bone,7 but also in cancellous bone. Cells made in the marrow for export to the circulation, which include preosteoclasts,7, 8 must traverse the thin wall of the branching sinusoids that empty into the central longitudinal vein.9 Structures resembling marrow sinusoids have been observed adjacent to trabeculae,10, 11 but they were not clearly demonstrated to be involved in bone remodeling. Hauge et al.6 have now identified a structure, which they refer to as the bone remodeling compartment (BRC), that resembles both the sinusoidal structures described by Burkhardt et al.10 and the canopy described by Bordier and Rasmussen.2 This structure is found almost exclusively at sites of bone remodeling. In the present paper this association was demonstrated in patients with primary hyperparathyroidism, but in earlier studies from this group the association was found also in renal osteodystrophy12 and osteoporosis.13 The cells forming the outer wall of the sinusoidal BRC, furthest from the bone and next to the marrow, were originally thought to be of endothelial origin,12 but these cells are negative for expression of CD34,6, 13, 14 von Willebrand factor,13, 14 and VEGF14 and positive for expression of alkaline phosphatase, osteocalcin, osteonectin,6 IGF-1 and −2,15, 16 TGF-β1, -β2, and -β3, and basic FGF.16 The cells are evidently of the osteoblast phenotype and are clearly the same cells as in the canopy of former bone lining cells described by Bordier and Rasmussen.2 To explain the full significance of these observations, it is necessary to distinguish between the vascular system, defined according to embryologic origin and current repertoire of gene expression, and the circulatory system, defined according to function. Ordinarily these are the same, but in some circumstances nonvascular cells may perform a circulatory function, referred to as vasculogenic mimicry.17 Like neoangiogenesis, this process is usually thought of in connection with the survival of neoplastic cells, but neoangiogenesis is an essential component of normal cortical bone remodeling,18 and it now appears that vasculogenic mimicry is an essential component of normal cancellous bone remodeling. Although final proof that the BRC performs a circulatory function is lacking, the circumstantial evidence for this conclusion is compelling. When originally seen12 they were believed to be sinusoids because their cells looked like endothelial cells, they contained numerous red cells (Fig. 1), and they resembled previously described paratrabecular sinusoids.10, 11 They are closely associated with marrow vessels14 with which they appear to communicate directly,19 and scanning electron microscopy (SEM) of vascular corrosion casts in lumbar vertebrae showed a close relationship between resorption cavities and vessels of diameter 10 to 15 μm.20 But the strongest reason for believing that the BRC has a circulatory function is that no other explanation is plausible for the presence of osteoclasts on the wrong side of the canopy (Fig. 1)! Bone remodeling compartment lying between bone marro