The reversal phase of the bone-remodeling cycle: cellular prerequisites for coupling resorption and formation

Abstract

The reversal phase couples bone resorption to bone formation by generating an osteogenic environment at remodeling sites. The coupling mechanism remains poorly understood, despite the identification of a number of 'coupling' osteogenic molecules. A possible reason is the poor attention for the cells leading to osteogenesis during the reversal phase. This review aims at creating awareness of these cells and their activities in adult cancellous bone. It relates cell events (i) on the bone surface, (ii) in the mesenchymal envelope surrounding the bone marrow and appearing as a canopy above remodeling surfaces and (iii) in the bone marrow itself within a 50-μm distance of this canopy. When bone remodeling is initiated, osteoprogenitors at these three different levels are activated, likely as a result of a rearrangement of cell-cell and cell-matrix interactions. Notably, canopies are brought under the osteogenic influence of capillaries and osteoclasts, whereas bone surface cells become exposed to the eroded matrix and other osteoclast products. In several diverse pathophysiological situations, including osteoporosis, a decreased availability of osteoprogenitors from these local reservoirs coincides with decreased osteoblast recruitment and impaired initiation of bone formation, that is, uncoupling. Overall, this review stresses that coupling does not only depend on molecules able to activate osteogenesis, but that it also demands the presence of osteoprogenitors and ordered cell rearrangements at the remodeling site. It points to protection of local osteoprogenitors as a critical strategy to prevent bone loss.

Figure 1

Remodeling unit in human iliac crest biopsy. Remodeling progresses to the left, as indicated by the time axis drawn relative to the bone surface. Histomorphometry indicates that a period of several weeks separates bone-resorbing osteoclasts from bone-forming osteoblasts (cells on osteoid beneath the blue line). This period is called reversal phase (demarcated by the dotted black lines). Mineralized matrix: blue; osteoid: red. Note the canopy of elongated cells (blue arrowhead) covering the bone-remodeling site. Image reproduced with permission.

Figure 2

Critical components of the reversal phase. (a) Cross-section at the starting point of a remodeling unit. The bone marrow envelope is lifted over an osteoclast on initiation of bone remodeling. BME: bone marrow envelope; BLC: bone-lining cell; OC: osteoclast; Rv.C: reversal cell. (b) Three-dimensional reconstruction of a bone resorption site in human iliac crest. The bone surface is shown in yellow, the canopy in semi-transparent purple and the capillary network in blue. OC: osteoclast (red cells on the bone surface). Note the close apposition between capillaries and the canopy. Bone-lining and reversal cells are not shown. Images reproduced with permission.

Figure 3

Osteoblast differentiation and proliferation at reversal sites. (a) Gradients of markers between canopy cells and reversal cells. Ki67: proliferation marker; P3NP: early differentiation marker. Data from ref. . (b and c) Gradients of markers between early (that is, next to the osteoclasts) and late (that is, next to osteoblasts depositing osteoid) reversal cells, and between active and arrested reversal cells. See text. Data from ref. .

Figure 4

Osteoblastogenesis at bone-remodeling sites. (a) Osteoblastogenesis routes. The reversal bone surface can be seen as a recruitment platform for pre-osteoblasts. Colonization originates from bone-lining cells and canopy cells (see ‘Reversal surfaces' and ‘Bone-remodeling compartment canopies', respectively). Final differentiation occurs on the bone surface, whereas proliferation occurs mainly in the canopy. Note the time axis: canopy cells triggered by osteoclasts (and capillaries) will later cover reversal surface, and later, bone-forming osteoblasts. OC: osteoclast. (b) Scheme drawing the attention on the proximity of osteogenic triggers (yellow lightning symbol) and osteoblast-lineage cells (blue) at the starting point of the remodeling cycle. Lighter and darker blue correspond to, respectively, less- and more-differentiated osteoblastic cells. The local convergence between these triggers and osteoprogenitors activates the process coupling resorption and formation. This model provides a simple explanation of why bone is replenished at the places where osteoclasts have removed it. BLC: bone-lining cell; OC: osteoclast; Rv.Cs: reversal cells.