Osteoporosis induced in mice by overproduction of interleukin 4.

Abstract

Osteoporosis is a common disease in which loss of bone mass results in skeletal fragility. The development of therapies for this disorder has been hampered by the lack of a convenient animal model. Here we describe a disorder in bone homeostasis in transgenic mice that inappropriately express the cytokine interleukin 4 (IL-4) under the direction of the lymphocyte-specific proximal promoter for the kck gene. Bone disease in Ick-IL-4 mice appeared to result from markedly decreased bone formation by osteoblasts, features strikingly similar to those observed in cases ofsevere low-turnover human involutional osteoporosis. By 2 months of age, female and male Ick-IL-4 mice invariably developed severe osteoporosis of both cortical and trabecular bone. Osteoporosis was observed in two independently derived founder animals, indicating that this phenotype was directly mediated by the IL-4 transgene.

Mouse cathepsin K: cDNA cloning and predominant expression of the gene in osteoclasts, and in some hypertrophying chondrocytes during mouse development

“…Northern analysis of mouse tissues for cathepsin K mRNA. Total RNA was isolated from the following mouse tissues: calvarial bone (lane 1), articular cartilage (2), auricular cartilage (3), nasal cartilage (4), pancreas (5), thymus (6), spleen (7), liver (8), kidney (9), brain (10), testis (11), heart (12), intestine (13), skin (14), lung (15), muscle (16), and eye (17). Denatured RNAs were electrophoresed, transferred by blotting onto the hybridization membrane and hybridized with the pMCatK-I probe (A) and with a probe for 28S rRNA (B).…”

“…Already several transgenic mice harboring different mutant transgenes are known where the balance between bone formation and resorption is affected. Osteoporosis, for example, has been observed in mice overexpressing the interleukin-4 [17] and TGF-[~2 genes [18]. Metaphyseal osteopenia has also been discovered in transgenic mice harboring a dominant negative mutation in the cartilage specific type II collagen gene [5].…”

osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification

“…Other engineered osteoporosis models involve overexpression of specific cytokines and growth factors. Ectopic overexpression of IL4 or TGF␤ in the bone have been reported to result in osteopenia, both of which are likely mediated by primary effects on osteoblast activity (Lewis et al 1993;Erlebacher and Derynck 1996). Overexpression of granulocyte colony-stimulating factor (GCSF) in transgenic mice leads to an osteoporosis-like phenotype attributable to an increase in osteoclast activity (Takahashi et al 1996).…”

“…IL1, IL3, IL4, IL6, and IL11 and several CSFs, including MCSF, have been implicated in the control of osteoclast development (Jilka et al 1992;Lewis et al 1993;Girasole et al 1994). Systemic hormones, such as parathyroid hormone and Vitamin D3, and local factors like tumor necrosis factor, promote the development of osteoclasts through their ability to stimulate production of cytokines like IL6 and IL11 by osteoblasts or their precursors (Kitazawa et al 1994;De La Mata et al 1995;Uy et al 1995).…”

Reduced cortical bone mass in mice with inactivation of interleukin‐4 and interleukin‐13

“…[12][13][14] Interestingly, overproduction of IL-4 in transgenic mice results in a low-turnover osteoporosis. 15 Thus, conflicting results regarding the role of IL-4 and IL-13 in the regulation of bone metabolism have been presented. The aim of the present study was to determine the in vivo role of endogenously produced physiological levels of IL-4 and IL-13 by comparing the skeletal phenotype of either IL-13…”