High Bone Resorption in Adult Aging Transgenic Mice Overexpressing Cbfa1/Runx2 in Cells of the Osteoblastic Lineage

Abstract

The runt family transcription factor core-binding factor ␣1 (Cbfa1) is essential for bone formation during development. Surprisingly, transgenic mice overexpressing Cbfa1 under the control of the 2.3-kb collagen type I promoter developed severe osteopenia that increased progressively with age and presented multiple fractures. Analysis of skeletally mature transgenic mice showed that osteoblast maturation was affected and that specifically in cortical bone, bone resorption as well as bone formation was increased, inducing high bone turnover rates and a decreased degree of mineralization. To understand the origin of the increased bone resorption, we developed bone marrow stromal cell cultures and reciprocal coculture of primary osteoblasts and spleen cells from wild-type or transgenic mice. We showed that transgenic cells of the osteoblastic lineage induced an increased number of tartrate-resistant acid phosphatase-positive multinucleated cells, suggesting that primary osteoblasts as well as bone marrow stromal cells from transgenic mice have stronger osteoclastogenic properties than cells derived from wild-type animals. We investigated the candidate genes whose altered expression could trigger this increase in bone resorption, and we found that the expression of receptor activator of NF-B ligand (RANKL) and collagenase 3, two factors involved in bone formation-resorption coupling, was markedly increased in transgenic cells. Our data thus suggest that overexpression of Cbfa1 in cells of the osteoblastic lineage does not necessarily induce a substantial increase in bone formation in the adult skeleton but has a positive effect on osteoclast differentiation in vitro and can also dramatically enhance bone resorption in vivo, possibly through increased RANKL expression.

TWIST Family of Basic Helix-Loop-Helix Transcription Factors Mediate Human Mesenchymal Stem Cell Growth and Commitment

“…Potential mechanisms may involve heightened expression of Runx2 in our TWIST-1 and DERMO-1 overexpressing MSC lines, whereas previous studies reported that high levels of Runx2 caused a reduction in the expression of target genes such as OCN, resulting in an inhibition of bone cell differentiation [47][48][49]. Alternatively, Twist-1 and Dermo-1 may be acting directly to inhibit the expression of genes such as OPN and BSP that contain putative of E-boxlike binding sites on their promoters (data not shown).…”

Lymphoid Enhancer Factor-1 and ॆ-Catenin Inhibit Runx2-dependent Transcriptional Activation of the Osteocalcin Promoter

“…Runx2 haploinsufficiency hinders intramembranous bone formation and causes the rare skeletal disorder, cleidocranial dysplasia (6). Interestingly, Runx2 overexpression induces bone fragility by blocking osteoblast differentiation and enhancing bone resorption (7,8).These genetic studies demonstrate that cellular control of Runx2 expression levels and function is crucial for skeletal development.At the molecular level, Runx2 activity is regulated by multiple transcriptional and post-translational mechanisms (9). Runx proteins activate or repress gene expression by binding the DNA sequence, TGPuGGTPu (10).…”

“…Runx2 haploinsufficiency hinders intramembranous bone formation and causes the rare skeletal disorder, cleidocranial dysplasia (6). Interestingly, Runx2 overexpression induces bone fragility by blocking osteoblast differentiation and enhancing bone resorption (7,8).…”

NAA10 controls osteoblast differentiation and bone formation as a feedback regulator of Runx2

“…However, later osteoblast maturation is not driven by these factors. For example, Runx2 transgenic mice have been found to show severe osteopenia with multiple fractures and depressed OCN in osteoblasts 28 . These findings suggest that Runx2 suppresses osteoblast maturation during the late differentiation stage.…”