Osteoblast-specific overexpression of human interleukin-7 rescues the bone mass phenotype of interleukin-7–deficient female mice

Abstract

Interleukin-7 is a critical cytokine for lymphoid development and a direct inhibitor of in vitro osteoclastogenesis in murine bone marrow cultures. To explore the role of IL-7 in bone, we generated transgenic mouse lines bearing the 2.3 Kb rat collagen 1A1 promoter driving the expression of human IL-7 specifically in osteoblasts. In addition we crossed these mice with IL-7 deficient mice to determine if the alterations in lymphopoiesis, bone mass and osteoclast formation observed in the IL-7 KO mice could be rescued by osteoblast-specific overexpression of IL-7. Here we show that mice overexpressing human IL-7 in the osteoblast lineage demonstrated increased trabecular bone volume in vivo by µCT and decreased osteoclast formation in vitro. Furthermore, targeted overexpression of IL-7 in osteoblasts rescued the osteopenic bone phenotype and B cell development of IL-7 KO mice but did not have an effect on T lymphopoiesis, which occurs in the periphery. The bone phenotypes in IL-7 KO mice and targeted IL-7 overexpressing mouse models were observed only in females. These results likely reflect both a direct inhibitory effects of IL-7 on osteoclastogenesis in vivo and gender specific differences in responses to IL-7.

Defective Endochondral Ossification-Derived Matrix and Bone Cells Alter the Lymphopoietic Niche in Collagen X Mouse Models

“…These data are consistent with those from several other mouse models that have either increased or decreased osteoblast numbers, or altered osteoblast quality/ function, which resulted in changes in B lymphopoiesis [14,17,19,20,22,23,59]. Moreover, a crosstalk between bone homeostasis and B cells that involves IL-7 and cytokine signaling has recently been documented [60,61]. Specifically, IL-7 null mice exhibit both a decrease in trabecular bone mass, as well as decreased numbers of early B cells.…”

“…Specifically, IL-7 null mice exhibit both a decrease in trabecular bone mass, as well as decreased numbers of early B cells. In contrast, mice that over-express human IL-7 in collagen I producing cells have both increased trabecular bone mass, as well as increased numbers of early B cells in the marrow [60]. Furthermore, crossing the IL-7 null mice with the Col-I IL-7 Tg mice results in a rescue in bone mass as well as a rescue of B cell numbers, and directly correlates an increase in bone mass with positive effects on B cells [60].…”

“…In contrast, mice that over-express human IL-7 in collagen I producing cells have both increased trabecular bone mass, as well as increased numbers of early B cells in the marrow [60]. Furthermore, crossing the IL-7 null mice with the Col-I IL-7 Tg mice results in a rescue in bone mass as well as a rescue of B cell numbers, and directly correlates an increase in bone mass with positive effects on B cells [60]. It has been proposed that under basal conditions, bone homeostasis is maintained via the ratio of the pro-osteoclastogenic factor receptor activator of nuclear factor kappa-b ligand (RANKL) and the anti-osteoclastogenic factor osteoprotegrin.…”

Hajdu Cheney Mouse Mutants Exhibit Osteopenia, Increased Osteoclastogenesis, and Bone Resorption

“…mice compared with controls, and most of the early osteoclastogenic activity resides in these cells (50,51). Further analysis of the monocyte/macrophage population present in the bone marrow B220 Ϫ CD3 Ϫ CD11b ϩ CD115 ϩ fraction revealed no difference in additional osteoclast precursor cells between Notch2 Q2319X and control mice.…”

“…Labeling of bone marrow cells for flow cytometric analysis was performed by standard staining procedures in Hanks' balanced salt solution (Life Technologies, Inc.) containing 0.01 M HEPES (pH 7.4), supplemented with 2% FBS. Flow cytometric analysis was carried out on a FACSCalibur instrument and data analysis performed using FlowJo software (Tree Star Inc., Ashland, OR) (51).…”