Heparan sulfate buffers the bone resorptive activity of Cathepsin K in bone homeostasis

mice display increased bone mass due to reduced bone resorptive activity of the mutant osteoclasts, opposite to the phenotype found under C57BL/6 background. This phenotype appears to reflect another biochemical property of HS-CtsK interaction, where HS can stabilize CtsK and extend its half-life. Combined, our data provide strong genetic evidence that CtsK-HS interaction is required for normal osteoclast activity in bone homeostasis through two mechanisms. Endogenous HS likely functions as a buffering agent to prevent excessive resorption and promote sustained resorption, and the balance point of the buffering can be greatly affected by genetic backgrounds.