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

To understand the physiological significance of the interaction between Cathepsin K (CtsK) and heparan sulfate (HS) in bone resorption, we manipulated HS-CtsK interaction genetically by mutating three basic residues of CtsK responsible for binding HS. This knockin strain (CtskAAA) expresses an HS-binding deficient CtsK variant. In contrast to CtsK-KO mice, which display profound osteopetrosis, under C57BL/6 background CtskAAA/AAA mice display an osteoporotic phenotype due to enhanced bone resorption by the mutant osteoclasts. This phenotype is consistent with our finding that HS inhibits the collagenase activity of CtsK, suggesting that HS functions as a restraining mechanism to dampen CtsK activity. Surprisingly, under 129S1 background, CtskAAA/AAA 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.