BoneKEy Reports | BoneKEy Watch

Activating cathepsin K in osteoclasts stimulates bone formation through S1P



DOI:10.1038/bonekey.2013.96

Osteoclasts are known to secrete cathepsin K (CTSK) during bone resorption. This cysteine protease activates tartrate-resistant acid phosphatase and degrades matrix collagen. In this study, knockout mice were generated to investigate the effects of Ctsk deletion in either osteoclasts or osteoblasts.

Targeting the Ctsk gene in osteoclasts did not have any adverse effect on skeletal development, but mice showed increased femoral bone mass, and increased trabecular number, cancellous bone mass and connective tissue density. Bone formation rate (BFR) was higher because of a higher mineral apposition rate. Osteoclast and osteoblast numbers both increased, as did the expression of Runx2, osterix, alkaline phosphatase (ALP) and osteopontin. In vitro, osteoclasts unable to express Ctsk showed higher levels of sphingosine-1-phosphate (S1P), ALP and mineralized nodules; all three effects could be blocked by an S1P1,3 receptor inhibitor.

Mice with a specific Ctsk knockout in osteoblasts had apparently normal levels of bone resorption and their BFR did not differ from controls. The RANKL/OPG ratio in osteoblasts was increased and the authors suggest this sets up a positive-feedback loop that boosts the number of osteoclasts still further.

Editor’s comment: Pycnodysostosis and treatment with some pharmacological inhibitors cause CTSK inactivation, resulting in inhibition of bone resorption and a simultaneous increase in bone formation, i.e. increased coupling. This seminal paper identifies a novel mechanism to explain why this occurs, i.e. through increased levels of S1P.


Creative Commons License This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 United States License.