Cathepsin K inhibitors promote osteoclast-osteoblast communication and engagement of osteogenesis

Cathepsin K inhibitors are well known for their inhibitory activity against bone resorption but were also reported to preserve bone formation in clinical trials, in contrast with other bone resorption antagonists. Here, we show cathepsin K inhibitors favor the crosstalk between osteoclasts and osteoblasts and help engaging the osteogenic process required for proper bone remodeling. Therefore, we used a novel approach, co-culturing human osteoclasts and osteoblast lineage cells on bone slices and monitoring through time-lapse their response to an active site (odanacatib) or an ectosteric (T06) cathepsin K inhibitor. Both inhibitors prevent the shift from pit to trench resorption mode and thus lead to a marked increase in pit-eroded surface lined with undigested collagen. Importantly, pit-eroded surfaces prove to receive significantly more and longer visits of osteoblast lineage cells. Furthermore, resorption achieved under CatK inhibition promotes osteoblast differentiation as shown by upregulation of alkaline phosphatase and type 1 collagen, and down regulation of RANKL. We propose a model where high cathepsin K activity levels lead to both aggressive bone resorption and compromised bone formation, and where low cathepsin K levels result in both slower resorption and faster initiation of formation. This model fits the current knowledge on the effect of collagen/collagenolysis on osteoclast activity and osteoblast chemotaxis. The combined effects of cathepsin K on resorption and formation render cathepsin K inhibitors unique tools to prevent bone loss. They stress the clinical interest of developing ectosteric inhibitors that may not have the side effects of active site inhibitors.