Cathepsin L‐deficient mice exhibit abnormal skin and bone development and show increased resistance to osteoporosis following ovariectomy

Abstract

The role of cathepsin L in normal physiological processes was assessed using cathepsin L homozygous knockout mice (B6;129-Ctsl(tm1Alpk)). These mice were generated using gene targeting in embryonic stem cells. Null mice fail to express mRNA and protein to cathepsin L. They developed normally and were fertile. The distinct phenotypic change exhibited was a progressive hair loss, culminating in extensive alopecia by 9 months of age. Histological analysis of the skin from homozygous mice revealed diffuse epithelial hyperplasia, hypotrichosis, hair shaft fragmentation and utricle formation. These findings provide evidence that cathepsin L is involved in the regulation of epithelial cell proliferation and differentiation in the skin. In addition, the role of cathepsin L in bone remodelling was evaluated. Using bone histomorphometric measurements, trabecular, but not cortical, bone volume was found to be significantly decreased in the cathepsin L heterozygote and homozygote mice compared to the wild-type mice. Following ovariectomy, it was observed that loss of trabecular bone, the most metabolically active component of bone, occurred to a lesser extent in homozygote, and heterozygote mice, than was seen in wild-type mice. These observations suggest that cathepsin L is likely to have a role in controlling bone turnover during normal development and in pathological states.

Pathophysiological Mechanism of Bone Loss in Type 2 Diabetes Involves Inverse Regulation of Osteoblast Function by PGC-1α and Skeletal Muscle Atrogenes: AdipoR1 as a Potential Target for Reversing Diabetes-Induced Osteopenia

“…It is possible that other atrogenes (atrogin-1 and cathepsin L) also play key roles in osteopenia induced by various stresses because these factors were also induced in db bones and glucoseand palmitate-treated MCOs. Other reports support such a notion, as mice lacking these atrogenes are protected from osteopenia under diverse stresses (45,46). In contrast, the muscle anabolic factor PGC-1a exhibited an agerelated decline in db mice.…”

Role of Cysteine Cathepsins in Joint Inflammation and Destruction in Human Rheumatoid Arthritis and Associated Animal Models

“…This reduction in bone mass may suggest that cathepsin L is involved in endochondral ossification [60]. This effect was reduced after ostrogen withdrawal by ovariectomy [60].…”

“…A cartilage phenotype of cathepsin K-deficient mice has not been reported. Furthermore, and in strong contrast to cathepsin K-deficient mice, cathepsin L knock out mice revealed a decrease in trabecular bone volume [60] (Table 1). This reduction in bone mass may suggest that cathepsin L is involved in endochondral ossification [60].…”

“…Furthermore, and in strong contrast to cathepsin K-deficient mice, cathepsin L knock out mice revealed a decrease in trabecular bone volume [60] (Table 1). This reduction in bone mass may suggest that cathepsin L is involved in endochondral ossification [60]. This effect was reduced after ostrogen withdrawal by ovariectomy [60].…”

“…No differences to arthritic wild-type mice Cathepsin K Yes [50] Yes [51] Osteopetrotic phenotype in long bones, trabelular and cortical bone mass is increased, higher brittleness of bone [52,53,54,55,56] hTNFtg mice: [57] Reduction of osteoclastdependent cartilage and bone destruction Adjuvant arthritis: [58] Reduction in pro- [47,48,49,51,59] Decrease in trabecular bone volume [60] Antigen-induced arthritis: [61] Impairment of Th cell response, reconstitution by expression of human cathepsin V in thymus Cathepsin S No Yes [47] No phenotypes reported…”