Abstract
Osteoclasts are terminally differentiated cells that attach to bone and secrete proteases to degrade the bone matrix. The primary protease responsible for the degradation of the organic component of the bone matrix is Cathepsin K, which was largely thought to be unique to osteoclasts. Given its apparent selective expression in osteoclasts, the Cathepsin K promoter has been engineered to drive the expression of Cre recombinase in mice and has been the most relevant tool for generating osteoclast-specific gene loss. In an effort to understand the role of the ARF tumor suppressor in osteoclasts, we crossed Arf fl/fl mice to CtskCre/+ mice, which unexpectedly resulted in the germline loss of Arf. We subsequently confirmed Cre activity in gametes by generating CtskCre/+; Rosa+ mice. These results raise significant concerns regarding in vivo bone phenotypes created using CtskCre/+ mice and warrant further investigation into the role of Cathepsin K in gametes as well as alternative tools for studying osteoclast-specific gene loss in vivo.
Highlights
Osteoclasts are bone-resorbing cells derived from the monocyte/macrophage family of the hematopoietic lineage [1]
Osteoclasts tightly attach to bone in order to create an acidic milieu, called the resorption lacunae, that is necessary for the degradation of both the inorganic and organic components of bone matrix
While we detected ARF in the testis of wild-type mice, we were unable to detect ARF protein expression in mice showing loss of exon1b at the DNA level (Fig. 2C). These results suggest that one copy of Cre under the control of the Cathepsin K (Ctsk) promoter is sufficient to cause nonspecific recombination and result in germline Arf loss
Summary
Osteoclasts are bone-resorbing cells derived from the monocyte/macrophage family of the hematopoietic lineage [1]. Cathepsin K is a lysosomal cysteine protease of the papain family and is the primary protease responsible for the degradation of type I collagen [2,3,4] In both humans and mice, Cathepsin K is highly expressed in osteoclasts. Expression of Cre mRNA in CtskCre/+ mice is thought to be unique to bone, with Cre activity reported only in osteoclasts [8]. This system is important to the field of bone biology as it is the most relevant tool for assessing osteoclast-specific gene alterations in vivo
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