An Ectosteric Inhibitor of Cathepsin K Inhibits Bone Resorption in Ovariectomized Mice

Preety Panwar, Liming Xue, Kent Søe, Kamini Srivastava, Simon Law, Jean-Marie Delaisse, Dieter Brömme*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review


The potent cathepsin K (CatK) inhibitor, Tanshinone IIA sulfonic sodium (T06), was tested for its in vitro and in vivo antiresorptive activities. T06 binds in an ectosteric site of CatK remote from its active site and selectively inhibits collagen degradation with an IC50 value of 2.7±0.2μM (CatK:T06 molar ratio of 1:5). However, it does not suppress fluorogenic peptide cleavage and gelatinolysis at a 2500-fold molar excess. Contrary to active site-directed CatK inhibitors, such as odanacatib, T06 suppresses bone resorption in both human and mouse osteoclasts equally well (IC50 value for human and mouse osteoclasts: 237±60nM and 245±55nM, respectively) and its antiresorptive activity is fully reversible in both cell types. Moreover, T06 affects neither the metabolic activity of osteoclasts nor osteoclastogenesis. In in vivo studies, 40mg T06/kg/d given to 12-week-old ovariectomized (OVX) mice for 3 months reduced plasma CTx-1 by 20% and increased osteoblast numbers and plasma P1NP by ∼28% when compared with the OVX control. μCT analysis of T06-treated OVX mice showed a 35% increase in bone mineral density and other femoral trabecular bone parameters when compared with OVX animals. T06 did not alter the number of osteoclasts, had no estrogenic effect on the uterus, did not change plasma estradiol levels, and did not inhibit fibroblast-mediated TGF-ß1 processing or degradation and cognitive functions in OVX mice. This study indicates that the ectosteric inhibitor, T06, is a selective antiresorptive CatK inhibitor that may overcome the shortcomings of side effect-prone active site-directed drugs, which all failed in clinical trials.

Original languageEnglish
JournalJournal of Bone and Mineral Research
Issue number12
Pages (from-to)2415-2430
Publication statusPublished - 15. Dec 2017


  • Animals
  • Bone Resorption/drug therapy
  • Cathepsin K/antagonists & inhibitors
  • Cattle
  • Cell Count
  • Female
  • Femur/pathology
  • Fibroblasts/metabolism
  • Humans
  • Mice, Inbred C57BL
  • Osteoblasts/drug effects
  • Osteoclasts/drug effects
  • Osteogenesis/drug effects
  • Ovariectomy
  • Protease Inhibitors/chemistry
  • Transforming Growth Factor beta1/metabolism

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