Bone density, strength, and formation in adult cathepsin K (-/-) mice.
Cathepsin K (CatK) is a cysteine protease expressed predominantly in osteoclasts, that plays a prominent role in degrading Type I collagen. Growing CatK null mice have osteopetrosis associated with a reduced ability to degrade bone matrix. Bone strength and histomorphometric endpoints in young adult CatK null mice aged more than 10 weeks have not been studied. The purpose of this paper is to describe bone mass, strength, resorption, and formation in young adult CatK null mice. In male and female wild-type (WT), heterozygous, and homozygous CatK null mice (total N=50) aged 19 weeks, in-life double fluorochrome labeling was performed. Right femurs and lumbar vertebral bodies 1-3 (LV) were evaluated by dual-energy X-ray absorptiometry (DXA) for bone mineral content (BMC) and bone mineral density (BMD). The trabecular region of the femur and the cortical region of the tibia were evaluated by histomorphometry. The left femur and sixth lumbar vertebral body were tested biomechanically. CatK (-/-) mice show higher BMD at the central and distal femur. Central femur ultimate load was positively influenced by genotype, and was positively correlated with both cortical area and BMC. Lumbar vertebral body ultimate load was also positively correlated to BMC. Genotype did not influence the relationship of ultimate load to BMC in either the central femur or vertebral body. CatK (-/-) mice had less lamellar cortical bone than WT mice. Higher bone volume, trabecular thickness, and trabecular number were observed at the distal femur in CatK (-/-) mice. Smaller marrow cavities were also present at the central femur of CatK (-/-) mice. CatK (-/-) mice exhibited greater trabecular mineralizing surface, associated with normal volume-based formation of trabecular bone. Adult CatK (-/-) mice have higher bone mass in both cortical and cancellous regions than WT mice. Though no direct measures of bone resorption rate were made, the higher cortical bone quantity is associated with a smaller marrow cavity and increased retention of non-lamellar bone, signs of decreased endocortical resorption. The relationship of bone strength to BMC does not differ with genotype, indicating the presence of bone tissue of normal quality in the absence of CatK.
Department of Molecular Endocrinology and Bone Biology, Merck Research Laboratories, WP26A-1000 West Point, PA 19486, USA. brenda_pennypacker@merck.com
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Pennypacker
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Shea
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Liu
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Masarachia
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Saftig
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Rodan
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Rodan
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Kimmel
D000818:Animals; D001696:Biomechanical Phenomena; D015519:Bone Density / Q000502:physiology*; D001862:Bone Resorption / Q000201:enzymology; D001842:Bone and Bones / Q000033:anatomy & histology / Q000201:enzymology* / Q000502:physiology*; D056657:Cathepsin K; D002403:Cathepsins / Q000172:deficiency* / Q000378:metabolism; D005260:Female; D005269:Femur / Q000033:anatomy & histology / Q000201:enzymology; D008159:Lumbar Vertebrae / Q000201:enzymology / Q000502:physiology; D008297:Male; D051379:Mice; D008856:Microscopy, Fluorescence; D009929:Organ Size; D010012:Osteogenesis; D012044:Regression Analysis; D012727:Sex Characteristics; D013499:Surface Properties
D002403:Cathepsins; D056657:Cathepsin K; C534132:Ctsk protein, mouse