Accelerated turnover of metaphyseal trabecular bone in mice overexpressingcathepsin K

This study is based on a hypothesis that overexpression of an osteoclast en zyme, cathepsin K, causes an imbalance in bone remodeling toward bone loss. The hypothesis was tested in transgenic (TG) mice harboring additional cop ies of the murine cathepsin K gene (Ctsk) identifiable by a silent mutation engineered into the construct. For this study, three TG mouse lines harbor ing 3-25 copies of the transgene were selected. Tissue specificity of trans gene expression was determined by Northern analysis, which revealed up to 6 -fold increases in the levels of cathepsin K messenger RNA (mRNA) in calvar ial and long bone samples of the three TG lines. No changes were seen in th e mRNA levels of other osteoclast enzymes, indicating that the increase in cathepsin K mRNA was not a reflection of activation of all osteoclast enzym es. Immunohistochemistry confirmed that cathepsin K expression in the TG mi ce was confined to osteoclasts and chondroclasts. Histomorphometry revealed a significantly decreased trabecular bone volume (BV), but, surprisingly, also a marked increase in the number of osteoblasts, the rate of bone turno ver, and the amount of mineralizing surface (MS). However, monitoring of bo ne density in the proximal tibias of the TG mice with peripheral quantitati ve computed tomography (pQCT) failed to reveal statistically significant ch anges in bone density. Similarly, no statistically significant alterations were observed in biomechanical testing at the age of 7 months. The increase s in parameters of bone formation triggered by increased cathepsin K expres sion is an example of the tight coupling of bone resorption and formation d uring the bone-remodeling cycle.