Proper bone remodeling necessarily requires that osteoblasts reconstruct the bone that osteoclasts have resorbed. However, the cellular events connecting resorption to reconstruction have remained poorly known. The consequence is a fragmentary understanding of the remodeling cycle where only the resorption and formation steps are taken into account. New tools have recently made possible to elucidate how resorption shifts to formation, thereby allowing to comprehend the remodeling cycle as a whole. This new knowledge is reviewed herein. It shows how teams of osteoclasts and osteoblast lineage cells are progressively established and how they are subjected therein to reciprocal interactions. Contrary to the common view, osteoclasts and osteoprogenitors are intermingled on the eroded surfaces. The analysis of the resorption and cell population dynamics shows that osteoprogenitor cell expansion and resorption proceed as an integrated mechanism; that a threshold cell density of osteoprogenitors on the eroded surface is mandatory for onset of bone formation; that the cell initiating osteoprogenitor cell expansion is the osteoclast; and that the osteoclast therefore triggers putative osteoprogenitor reservoirs positioned at proximity of the eroded bone surface (bone lining cells, canopy cells, pericytes). The interplay between magnitude of resorption and rate of cell expansion governs how soon bone reconstruction is initiated and may determine uncoupling and permanent bone loss if a threshold cell density is not reached. The clinical perspectives opened by these findings are discussed.

Women gradually lose bone from the age of ~35 years, but around menopause, the rate of bone loss escalates due to increasing bone resorption and decreasing bone formation levels, rendering these individuals more prone to developing osteoporosis. The increased osteoclast activity has been linked to a reduced estrogen level and other hormonal changes. However, it is unclear whether intrinsic changes in osteoclast precursors around menopause can also explain the increased osteoclast activity. Therefore, we set up a protocol in which CD14⁺blood monocytes were isolated from 49 female donors (40–66 years old). Cells were differentiated into osteoclasts, and data on differentiation and resorption activity were collected. Using multiple linear regression analyses combining in vitro and in vivo data, we found the following: (1) age and menopausal status correlate with aggressive osteoclastic bone resorption in vitro; (2) the type I procollagen N-terminal propeptide level in vivo inversely correlates with osteoclast resorption activity in vitro; (3) the protein level of mature cathepsin K in osteoclasts in vitro increases with age and menopause; and (4) the promoter of the gene encoding the dendritic cell-specific transmembrane protein is less methylated with age. We conclude that monocytes are “reprogrammed” in vivo, allowing them to “remember” age, the menopausal status, and the bone formation status in vitro, resulting in more aggressive osteoclasts. Our discovery suggests that this may be mediated through DNA methylation. We suggest that this may have clinical implications and could contribute to understanding individual differences in age- and menopause-induced bone loss.

Osteoclasts (OCs) seeded on bone slices either drill round pits or dig long trenches. Whereas pits correspond to intermittent resorption, trenches correspond to continuous and faster resorption and require a distinct assembly of the resorption apparatus. It is unknown whether the distinction between pits and trenches has any biological relevance. Using OCs prepared from different blood donors, we found that female OCs achieved increased resorption mainly through pit formation, whereas male OCs did so through trench formation. Trench formation went along with high collagenolytic activity and high cathepsin K (CatK) expression, thereby allowing deeper demineralization. A specific CatK inhibitor abrogated the generation of trenches, while still allowing the generation of pits. OCs obtained from bone marrow were more prone to generate trenches than those obtained from blood. Scanning electron microscopy of bone surfaces eroded in vivo showed trenches and pits of similar size as those made by OCs in culture. We conclude that the distinction between trench- and pit-forming OCs is relevant to the differences among OCs from different skeletal sites, different individuals, including gender, and results from differences in collagenolytic power. This indicates a biological relevance and highlights the importance of discriminating between pits and trenches when assessing resorption.

Osteoclasts are known to exert their resorptive activity through a so-called resorption cycle consisting of alternating resorption and migration episodes and resulting typically in the formation of increasing numbers of discrete round excavations on bone slices. This study shows that glucocorticoids deeply modify this resorptive behavior. First, glucocorticoids gradually induce excavations with a trenchlike morphology while reducing the time-dependent increase in excavation numbers. This indicates that glucocorticoids make osteoclasts elongate the excavations they initiated rather than migrating to a new resorption site, as in control conditions. Second, the round excavations in control conditions contain undegraded demineralized collagen as repeatedly reported earlier, whereas the excavations with a trenchlike morphology generated under glucocorticoid exposure appear devoid of leftovers of demineralized collagen. This indicates that collagenolysis proceeds generally at a lower rate than demineralization under control conditions, whereas collagenolysis rates are increased up to the level of demineralization rates in the presence of glucocorticoids. Taking these observations together leads to a model where glucocorticoid-induced increased collagenolysis allows continued contact of osteoclasts with mineral, thereby maintaining resorption uninterrupted by migration episodes and generating resorption trenches. In contrast, accumulation of demineralized collagen, as prevails in controls, acts as a negative-feedback loop, switching resorptive activity off and promoting migration to a new resorption site, thereby generating an additional resorption pit. We conclude that glucocorticoids change the osteoclastic resorption mode from intermittent to continuous and speculate that this change may contribute to the early bone fragilization of glucocorticoid-treated patients. © 2010 American Society for Bone and Mineral Research.