Jensen, Pia Rosgaard7; Andersen, Thomas Levin8; Pennypacker, Brenda L4; Duong, Le T5; Engelholm, Lars H9; Delaissé, Jean-Marie6
1 Biocomplexity, The Niels Bohr Institute, Faculty of Science, Københavns Universitet2 Engelholm Group, BRIC Research Groups, BRIC, Københavns Universitet3 Xray and Neutron Science, The Niels Bohr Institute, Faculty of Science, Københavns Universitet4 Bone Biology Group, Merck Research Laboratories, West Point, PA 19486, USA. Electronic address: firstname.lastname@example.org Bone Biology Group, Merck Research Laboratories, West Point, PA 19486, USA. Electronic address: email@example.com Klinisk Cellebiologisk Afdeling7 Xray and Neutron Science, The Niels Bohr Institute, Faculty of Science, Københavns Universitet8 Biocomplexity, The Niels Bohr Institute, Faculty of Science, Københavns Universitet9 Engelholm Group, BRIC Research Groups, BRIC, Københavns Universitet
lessons from two bone resorption inhibitors affecting bone formation differently
The bone matrix is maintained functional through the combined action of bone resorbing osteoclasts and bone forming osteoblasts, in so-called bone remodeling units. The coupling of these two activities is critical for securing bone replenishment and involves osteogenic factors released by the osteoclasts. However, the osteoclasts are separated from the mature bone forming osteoblasts in time and space. Therefore the target cell of these osteoclastic factors has remained unknown. Recent explorations of the physical microenvironment of osteoclasts revealed a cell layer lining the bone marrow and forming a canopy over the whole remodeling surface, spanning from the osteoclasts to the bone forming osteoblasts. Several observations show that these canopy cells are a source of osteoblast progenitors, and we hypothesized therefore that they are the likely cells targeted by the osteogenic factors of the osteoclasts. Here we provide evidence supporting this hypothesis, by comparing the osteoclast-canopy interface in response to two types of bone resorption inhibitors in rabbit lumbar vertebrae. The bisphosphonate alendronate, an inhibitor leading to low bone formation levels, reduces the extent of canopy coverage above osteoclasts. This effect is in accordance with its toxic action on periosteoclastic cells. In contrast, odanacatib, an inhibitor preserving bone formation, increases the extent of the osteoclast-canopy interface. Interestingly, these distinct effects correlate with how fast bone formation follows resorption during these respective treatments. Furthermore, canopy cells exhibit uPARAP/Endo180, a receptor able to bind the collagen made available by osteoclasts, and reported to mediate osteoblast recruitment. Overall these observations support a mechanism where the recruitment of bone forming osteoblasts from the canopy is induced by osteoclastic factors, thereby favoring initiation of bone formation. They lead to a model where the osteoclast-canopy interface is the physical site where coupling of bone resorption to bone formation occurs.
Biochemical and Biophysical Research Communications, 2014, Vol 443, Issue 2, p. 694-9
Animals; Bone Matrix; Bone Remodeling; Bone Resorption; Computer Simulation; Models, Biological; Osteoclasts; Rabbits; Spine