Overexpression of Cbfa1 in osteoblasts inhibits osteoblast maturation and causes osteopenia with multiple fractures

Abstract

Targeted disruption of core binding factor α1 (Cbfa1) showed that Cbfa1 is an essential transcription factor in osteoblast differentiation and bone formation. Furthermore, both in vitro and in vivo studies showed that Cbfa1 plays important roles in matrix production and mineralization. However, it remains to be clarified how Cbfa1 controls osteoblast differentiation, bone formation, and bone remodelling. To understand fully the physiological functions of Cbfa1, we generated transgenic mice that overexpressed Cbfa1 in osteoblasts using type I collagen promoter. Unexpectedly, Cbfa1 transgenic mice showed osteopenia with multiple fractures. Cortical bone, which was thin, porous, and enriched with osteopontin, was invaded by osteoclasts, despite the absence of acceleration of osteoclastogenesis. Although the number of neonatal osteoblasts was increased, their function was impaired in matrix production and mineralization. Furthermore, terminally differentiated osteoblasts, which strongly express osteocalcin, and osteocytes were diminished greatly, whereas less mature osteoblasts expressing osteopontin accumulated in adult bone. These data indicate that immature organization of cortical bone, which was caused by the maturational blockage of osteoblasts, led to osteopenia and fragility in transgenic mice, demonstrating that Cbfa1 inhibits osteoblast differentiation at a late stage.

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).…”

Increased dosage of Runx1/AML1 acts as a positive modulator of myeloid leukemogenesis in BXH2 mice

“…Insufficient downregulation of RUNX1 due to the increased dose at a certain stage of megakaryocyte differentiation may result in disturbed regulation of cell proliferation and could eventually give rise to TAM, then leukemia. Consistent with this notion, Runx2 Tg mice which overexpress Runx2 also showed impaired differentiation of T-cell or bone development (Vaillant et al, 1999;Liu et al, 2001). On the other hand, another mechanism, a constitutive expression of RUNX1 that may be caused by an increased dose should be considered carefully, since RUNX1 is shown to be regulated in a cell-cycledependent manner (Bernardin-Fried et al, 2004).…”

Influence of the ratio of particulate autogenous bone graft/platelet-rich plasma on bone healing in critical-size defects: A histologic and histometric study in rat calvaria

“…In a recent in vivo study, Nagata et al 25 demonstrated that a large volume of PRP combined with autogenous bone graft decreased the expression of osteopontin. Because osteopontin is related to osteoblast function, 26,27 this seems to indicate that a large volume of PRP may have a cytotoxic effect on graft healing. A large volume of PRP may also form a clot that could restrict vascular flow inside the graft and decrease the number of bone cells.…”