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Cathepsin K: The Action in and Beyond Bone
Rongchen Dai1, Zeting Wu2, Hang Yin Chu1
1Law Sau Fai Institute for Advancing Translational Medicine in Bone & Joint Diseases, Hong Kong Baptist University, Hong Kong, China.
Abstract:
Cathepsin K (CatK) is one of the most potent proteases in lysosomal cysteine proteases family, of which main function is to mediate bone resorption. Currently, CatK is among the most attractive targets for anti-osteoporosis drug development. Although many pharmaceutical companies are working on the development of selective inhibitors for CatK, there is no FDA approved drug till now. Odanacatib (ODN) developed by Merck & Co. is the only CatK inhibitor candidate which demonstrated high therapeutic efficacy in patients with postmenopausal osteoporosis in Phase III clinical trials. Unfortunately, the development of ODN was finally terminated due to the cardio-cerebrovascular adverse effects. Therefore, it arouses concerns on the undesirable CatK inhibition in non-bone sites. It is known that CatK has far-reaching actions throughout various organs besides bone. Many studies have also demonstrated the involvement of CatK in various diseases beyond the musculoskeletal system. This review not only summarized the functional roles of CatK in bone and beyond bone, but also discussed the potential relevance of the CatK action beyond bone to the adverse effects of inhibiting CatK in non-bone sites.
Insights
Cathepsin K (CatK) is crucial for bone resorption and a target for osteoporosis drugs. However, inhibiting CatK may cause side effects due to its roles beyond bone.
Area of Science:
- Biochemistry
- Pharmacology
- Pathology
Background:
- Cathepsin K (CatK) is a potent lysosomal cysteine protease primarily involved in bone resorption.
- It is a key target for developing anti-osteoporosis therapies.
- Current development faces challenges due to potential adverse effects.
Purpose of the Study:
- To review the functional roles of Cathepsin K (CatK) in both bone and non-bone tissues.
- To discuss the implications of CatK's extra-skeletal functions on the safety of CatK inhibitors.
Main Methods:
- Literature review of studies on Cathepsin K (CatK) function.
- Analysis of clinical trial data for CatK inhibitors, including Odanacatib.
- Synthesis of information on CatK's roles in various organs and diseases.
Main Results:
- Cathepsin K (CatK) plays significant roles in bone resorption and is a promising target for osteoporosis.
- Odanacatib, a selective CatK inhibitor, showed efficacy but was halted due to cardiovascular risks.
- CatK has diverse functions in multiple organs, suggesting potential off-target effects.
Conclusions:
- Understanding CatK's non-bone functions is critical for developing safe and effective osteoporosis treatments.
- Further research is needed to balance therapeutic benefits with potential adverse effects of CatK inhibition.
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