Bromme Lab Has Found a Potential Osteoporosis Treatment in Compound Derived from Traditional Chinese Medicine

Corrie BelangerBy Corrie Belanger, PhD Candidate, Hancock Lab

Bone deteriorating diseases such as osteoporosis affect at least 1 in 3 women and 1 in 5 men in their lifetimes, causing increased risks of fractures, and potentially leading to disfigurement and decreased mobility or independence1. As a result, the annual economic burden of osteoporosis in Canada is estimated to be $4.6 billion2. One approach to treating this disease has focused on inhibition of the collagen-degrading protease capthesin K (CatK). This protein is located in cells responsible for resorbing bone tissue, both during growth and healing, and in bone wasting diseases. Most of the compounds that effectively inhibit CatK bone resorption target the enzyme’s active site, but none of them have been approved for clinical use due to negative side effects caused by off-target inhibition of other CatK activities. Researchers in the Bromme lab instead chose to focus on compounds that selectively inhibit the collagen-degrading activity of this enzyme by targeting a separate binding site, the ectosteric site. This approach could make treatments more therapeutically relevant without the various side effects associated with inhibition of the enzyme’s active site. Their work was published in the Journal of Bone and Mineral Research in July 2017. Preety Panwar and her colleagues demonstrated the anti bone-resorptive activity of a compound found in traditional Chinese medicine, targeting an ectosteric site in CatK.

Figure 1. T06 binding at ectosteric site on CatK

The Bromme lab identified the compound Tanshinone IIA sulfonic sodium (T06) in a screen of 31 derivatives of a natural component of the red sage plant, which is used in traditional Chinese medicine to treat bone and cardiovascular diseases. Amazingly, T06 inhibits CatK degradation of soluble and insoluble collagen without affecting other activities of CatK. With molecular analysis, Panwar et al. predicted that T06 favorably binds CatK in an ectosteric site, while leaving the enzyme’s active site unbound (Figure 1). This anti-resorptive inhibition of CatK was also determined to be reversible upon removal of the compound, and growth of new bone developing cells was not altered by this treatment. The latter was demonstrated in cultured cells, as well as in a mouse model of osteoporosis, where treatment with T06 had no effect on numbers of bone producing cells but successfully restored bone structure and increased bone formation, compared to untreated mice.

With significant and reversible CatK collagenase inhibition, lack of active site inhibition, and therapeutic activity in mouse models of osteoporosis, T06 is a promising compound for the treatment of bone deteriorating conditions. Indeed, the research done by Panwar et al. also supports the development of ectosteric inhibitors as a viable alternative to active-site inhibitors for treatment of collagenase activity of CatK in skeletal diseases.

 

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