A Critical Role of the Bone Marrow Envelope in Human Bone Remodeling

Abstract

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 gained 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, smooth muscle actin (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. Importantly, the high proliferation index in the canopy is not associated with increasing cell densities at the canopy level, but it is 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 the same functional unit, and propose that the bone marrow envelope is critical for preserving bone health. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Disturbed bone marrow adiposity in patients with Cushing’s syndrome and glucocorticoid- and postmenopausal- induced osteoporosis

“…In physiological conditions, the microscopic basic multicellular units (BMUs), which consist of a tightly regulated sequence of events including an initial osteoclastic bone resorption, a reversalresorption phase and an osteoblastic bone formation phase, maintain bone homeostasis (15). On trabecular and endocortical bone surfaces, the BMUs operate on the bone surfaces separated from the bone marrow cavity by bone marrow envelope cells, forming a bone remodeling compartment canopy above remodeling sites (16)(17)(18). Several studies have proposed that this envelope/canopy is a local reservoir of osteoprogenitors that are delivered to eroded surfaces, where they can further differentiate into mature bone-forming osteoblasts (19).…”

Novel Developments in the Treatment of Multiple Myeloma-Associated Bone Disease

“…Myeloma bone disease is characterized by the development of focal "punch-out" lesions, which are the result of a highly active bone resorption with an uncoupling of the subsequent bone formation. The uncoupled bone formation is likely a consequence of myeloma cell-induced disruption of the bone remodeling compartment (BRC) canopies (Figure 3), which reflect a bone marrow envelope that is lifted above remodeling sites [84]. The canopies/envelope consist of elongated osteoprogenitor cells that physically separate the bone surface cells, including remodeling events from the bone marrow cavity [10,85], considered to be a local reservoir of osteoprogenitor cells [84,86].…”

“…The uncoupled bone formation is likely a consequence of myeloma cell-induced disruption of the bone remodeling compartment (BRC) canopies (Figure 3), which reflect a bone marrow envelope that is lifted above remodeling sites [84]. The canopies/envelope consist of elongated osteoprogenitor cells that physically separate the bone surface cells, including remodeling events from the bone marrow cavity [10,85], considered to be a local reservoir of osteoprogenitor cells [84,86]. This local reservoir is critical for the transition from bone erosion to formation, requiring the recruitment of a critical density of osteoprogenitor cells to the eroded surfaces formed by bone-resorbing osteoclasts.…”