A critical role of the bone marrow envelope in human bone remodeling.

Proper bone remodeling depends not only on a team of bone-resorbing osteoclasts and bone-forming osteoblasts. It also depends on the site-specific delivery of a large amount of osteoblast lineage cells to the bone remodeling site. How this delivery occurs is poorly known. Here, we got insight into this mechanism by analyzing the distribution of markers of osteoblastogenesis on bone surfaces and in their bone marrow neighborhood in human cancellous bone. We found a CD271-positive/PDGFβ-R-positive cell layer surrounding the bone marrow, that provides osteoblastogenic potential along all bone surfaces whether quiescent or remodeling. This bone marrow envelope cell layer takes the appearance of a canopy above remodeling sites, where it then also shows an upregulation of the proliferation marker Ki67, SMA, Tenascin-C, fibronectin and MMP13. This indicates that the canopy is a region of the bone marrow envelope where early markers of osteoblastogenesis are activated concurrently with initiation of bone remodeling. Important, the high proliferation index in the canopy is not associated with increasing cell densities at the canopy level, but well at the bone surface level, thereby supporting delivery of cells from the canopy to the bone surface. This delivery route explains why lack of canopies was previously found to coincide with lack of bone formation, and fits current knowledge on the canopies as a target for regulators of bone remodeling. We conclude that the coordination of bone marrow envelope activities and bone surface activities allows integrating osteoblastogenesis and bone remodeling into a same functional unit, and propose that the bone marrow envelope is critical for preserving bone health.