Increased fracture callus mineralization and strength in cathepsin K knockout mice |
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| Affiliation: | 1. Bone Biology Group, Merck Research Laboratories, West Point, PA, USA;2. New England Musculoskeletal Institute, University of Connecticut Health Center, Farmington, CT, USA;3. Charles River Laboratories, Preclinical Services, Montreal, Quebec, Canada;1. Department of Radiology, University of California, San Diego, CA, USA;2. Shiley Center for Orthopaedic Research & Education, Scripps Clinic, La Jolla, CA, USA;3. Department of Radiology, Hua Dong Hospital, Fudan University, Shanghai, PR China;4. Department of Radiology, VA San Diego Healthcare System, La Jolla, CA, USA;1. Department of Endodontology and Operative Dentistry, Faculty of Dental Science, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan;2. Department of Endodontology, Kyushu University Hospital, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan;3. Colgate Australian Clinical Dental Research Centre, School of Dentistry, University of Adelaide, SA 5005, Australia;1. Department of Mechanical Engineering, University of Delaware, Newark, DE 19716, USA;2. Department of Biomedical Engineering, University of Delaware, Newark, DE 19716, USA;1. Shriners Hospitals for Children-Chicago, Chicago, IL, USA;2. Department of Biomedical Engineering, Marquette University, Orthopaedic and Rehabilitation Engineering Center (OREC), Milwaukee, WI, USA;3. Advanced Light Source, Lawrence Berkeley National Laboratory, Berkeley, CA, USA;4. Department of Orthopedic Surgery, Rush University Medical Center, Chicago, IL, USA;1. Orthopaedic Research Laboratories, University of Michigan, Room 2003 Biomedical Sciences Research Building, 109 Zina Pitcher Place, Ann Arbor, MI 48109, USA;2. Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, 1011 North University Ave., Ann Arbor, MI 48109, USA;3. Department of Clinical Studies-New Bolton Center, School of Veterinary Medicine, University of Pennsylvania, Room 145 Myrin Bldg, Kennett Square PA;4. Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia PA |
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| Abstract: | Cathepsin K (CatK) is a cysteine protease, expressed predominantly in osteoclasts (OC) which degrades demineralized bone matrix. Novel selective inhibitors of CatK are currently being developed for the treatment of postmenopausal osteoporosis. Pharmacological inhibition of CatK reduces OC resorption activity while preserving bone formation in preclinical models. Disruption of the CatK gene in mice also results in high bone mass due to impaired bone resorption and elevated formation. Here, we assessed mid-shaft femoral fracture healing in 8–10 week old CatK knock-out (KO) versus wild type (WT) mice. Fracture healing and callus formation were determined in vivo weekly via X-ray, and ex vivo at days 14, 18, 28 and 42 post-fracture by radiographic scoring, micro-computed tomography (μCT), histomorphometry and terminal mechanical four point bend strength testing. Radiological evaluation indicated accelerated bone healing and remodeling for CatK KO animals based on increased total radiographic scores that included callus opacity and bridging at days 28 and 42 post-fracture. Micro-CT based total callus volume was similar in CatK KO and WT mice at day 14. Callus size in CatK KO mice was 25% smaller than that in WT mice at day 18, statistically significant by day 28 and exhibited significantly higher mineralized tissue volume and volumetric BMD as compared to WT by day 18 onward. Osteoclast surface and osteoid surface trended higher in CatK KO calluses at all time-points and osteoblast number was also significantly increased at day 28. Increased CatK KO callus mineral density was reflected in significant increases in peak load and stiffness over WT at day 42 post-fracture. Regression analysis indicated a positive correlation (r = 0.8671; p < 0.001) between callus BMC and peak load indicating normal mineral properties in CatK KO calluses. Taken together, gene deletion of cathepsin K in mice accelerated callus size resolution, significantly increased callus mineralized mass, and improved mechanical strength as compared to wild type mice. |
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