A Physical Mechanism for Coupling Bone Resorption and Formation in Adult Human Bone

Abstract

During skeletal remodeling, pre-osteoclasts and pre-osteoblasts are targeted to critical sites of the bone to resorb and reconstruct bone matrix, respectively. Coordination of site-specific recruitment of these two cell types is a prerequisite to maintain the specific architecture of each bone within strict limits throughout adult life. Here, we determined that the bone marrow microanatomy adjacent to remodeling areas is a central player in this process. By using histomorphometry and multiple immunostainings, we demonstrated in biopsies exhibiting coupled bone resorption and formation that osteoclasts and osteoblasts on the bone surface were always covered by a canopy of flat cells expressing osteoblast markers. In contrast, in biopsies in which this canopy was disrupted, bone formation was deficient. Three-dimensional visualizations revealed that this canopy covered the entire remodeling site and was associated with capillaries, thereby forming a previously unrecognized microanatomical entity. Furthermore, pre-osteoclasts were positioned along these capillaries. These findings led to a model that implicates vasculature in the site-specific recruitment of osteoclasts and osteoblasts and embraces the current knowledge on the molecular mechanism of bone remodeling.

Increased Lipid Oxidation Causes Oxidative Stress, Increased Peroxisome Proliferator-activated Receptor-γ Expression, and Diminished Pro-osteogenic Wnt Signaling in the Skeleton

“…This evidence is consistent with previous reports that activation of PPAR␥ with synthetic thiazolidinedione ligands in vitro (5,34,49) and in rodents (5,50,51) cause reciprocal changes in osteoblast and adipocyte differentiation. Moreover, patients receiving thiazolidinediones for the management of type II diabetes exhibit decreased bone mass and increased incidence of fractures (52)(53)(54). Taken together, our results support the view that the combined effects of increased lipid oxidation, PPAR␥ expression, and reduced Wnt signaling that occur with advancing age favor adipogenesis at the expense of osteoblastogenesis.…”

Osteoblasts in osteoporosis: past, emerging, and future anabolic targets

“…Although the exact location of MSC in vivo is still in debate, recent evidence suggests that some of these cells are pericytes located on the outer surface of blood vessels and sinusoids in the bone marrow (8). Also, recent studies suggest that MSC reach bone surfaces from the circulation through vascular channels in association with bone remodeling sites (9). Once they arrive at the bone surface, osteoblastic cells produce bone matrix that becomes mineralized.…”

Cellular and Molecular Mechanisms of Bone Remodeling

“…Evidence in humans suggests that it is a bone-lining cell, whereas in the mouse, osteomacs traverse BMUs during physiological bone remodeling (34). Functionally, it has been proposed that the canopy structure, and subsequent bone-remodeling compartment, generates a unique microenvironment to facilitate "coupled" osteoclast resorption and osteoblast formation and ensures minimal net change in bone volume during physiological bone remodeling (35).…”