Low peak bone mass and attenuated anabolic response to parathyroid hormone in mice with an osteoblast-specific deletion of connexin43

Abstract

Connexin43 (Cx43) is involved in bone development, but its role in adult bone homeostasis remains unknown. To overcome the postnatal lethality of Cx43 null mutation, we generated mice with selective osteoblast ablation of Cx43, obtained using a Cx43fl allele and a 2.3-kb fragment of the α1(I) collagen promoter to drive Cre in osteoblasts (ColCre). Conditionally osteoblast-deleted ColCre;Cx43–/fl mice show no malformations at birth, but develop low peak bone mass and remain osteopenic with age, exhibiting reduced bone formation and defective osteoblast function. By both radiodensitometry and histology, bone mineral content increased rapidly and progressively in adult Cx43+/fl mice after subcutaneous injection of parathyroid hormone (PTH), an effect significantly attenuated in ColCre;Cx43–/fl mice, with Cx43–/fl exhibiting an intermediate response. Attenuation of PTH anabolic action was associated with failure to increase mineral apposition rate in response to PTH in ColCre;Cx43–/fl, despite an increased osteoblast number, suggesting a functional defect in Cx43-deficient bone-forming cells. In conclusion, lack of Cx43 in osteoblasts leads to suboptimal acquisition of peak bone mass, and hinders the bone anabolic effect of PTH. Cx43 represents a potential target for modulation of bone anabolism.

Connexin43 Potentiates Osteoblast Responsiveness to Fibroblast Growth Factor 2 via a Protein Kinase C-Delta/Runx2–dependent Mechanism

“…These Cx43-deficient mice die at birth because of a defect in cardiac function (Reaume et al, 1995). Recently, conditional deletion of Cx43 in cells of osteogenic lineage has revealed an important role for Cx43 in postnatal skeletal homeostasis as well (Chung et al, 2006). These conditional Cx43 knockout mice, which use a 2.3-kb collagen I promoter-driven Cre-recombinase to excise a floxed Cx43 allele in cells of the osteoblast lineage, exhibit severe osteopenia as a result of defective osteoblast function.…”

“…There is both in vivo and in vitro evidence that manipulating the relative abundance of Cx43 can affect osteoblast function. A gene dosage effect is observed using a model of conditional knockout of Cx43 in osteoblasts, as the anabolic response to PTH in heterozygous Cx43 Ϫ/fl mice is intermediate between wild-type and Cx43 conditionally deleted animals (Chung et al, 2006). Similarly, heterozygous Cx43 Ϫ/fl mice demonstrate an intermediate response to mechanical load (Grimston et al, 2008).…”

Mechanical strain induces Cx43 expression in spinal ligament fibroblasts derived from patients presenting ossification of the posterior longitudinal ligament

“…calcium ions, inositol phosphates and cyclic nucleotides) to pass from cell to cell [9,10]. Several researchers have described the existence of gap junctions between bone cells [11,12]. Although other connexins can be expressed in osteoblastic cells, gap-junctional intercellular communication between these cells correlates best with Cx43 expression.…”

“…It has been shown that Cx43 is abundantly expressed in both osteoblasts and osteocytes, where it can transmit hormonal signals, mechanical load and growth factor cues among cells to coordinate the synthesis of new bone [19]. Over the past two decades, many studies have described a role for Cx43 intercellular communication in the proliferation and differentiation of osteoblasts and bone cells [11,12,[20][21][22]. Recently, conditional deletion of Cx43 in cells of osteogenic lineage has revealed an Indeed, we detected a significant up-regulation of Cx43 in OPLL ligament fibroblasts at 12 and 24 h after mechanical strain loading in comparison with static conditions, and there were no changes in non-OPLL cells.…”

“…This mode of cell-cell communication is of particular importance in the skeleton, where a large variety of systemic and locally generated signals are transduced into biological signals and transmitted to cells at specific locations to permit bone formation [10]. As such, mineralization in Cx43 null osteoblasts, as well as flawed osteoblastic responses to anabolic signals, has been reported [11,12].…”