Noggin Suppression Enhances in Vitro Osteogenesis and Accelerates in Vivo Bone Formation

Abstract

Several investigations have demonstrated a precise balance to exist between bone morphogenetic protein (BMP) agonists and antagonists, dictating BMP signaling and osteogenesis. We report a novel approach to manipulate BMP activity through a down-regulation of the potent BMP antagonist Noggin, and examined the effects on the bone forming capacity of osteoblasts. Reduction of noggin enhanced BMP signaling and in vitro osteoblast bone formation, as demonstrated by both gene expression profiles and histological staining. The effects of noggin suppression on in vivo bone formation were also investigated using critical-sized calvarial defects in mice repaired with noggin-suppressed osteoblasts. Radiographic and histological analyses revealed significantly more bone regeneration at 2 and 4 weeks post-injury. These findings strongly support the concept of enhanced osteogenesis through a down-regulation in Noggin and suggest a novel approach to clinically accelerate bone formation, potentially allowing for earlier mobilization of patients following skeletal injury or surgical resection.

The BMP2 variant L51P restores the osteogenic differentiation of human mesenchymal stromal cells in the presence of intervertebral disc cells

“…Instead, molecule-based techniques, such as suppression by small interfering RNA (siRNA), cognate antibody or conditional deletion could be used to address the effect of individual BMP antagonists (Ghadakzadeh et al, 2016). For instance, Noggin siRNA-transfected osteoblasts, that were implemented into calvarial critical size defect, showed enhanced bone regeneration as compared to control osteoblasts (Wan et al, 2007). Same results, using a similar knock-down approach, were achieved for adipose-derived MSCs (Fan et al, 2013).…”

“…Wan et al showed that NOG suppression by small interfering RNA (siRNA) in MC3T3-T1 cells and mice calvarial osteoblasts enhanced the cells osteogenic differentiation potential. In addition, NOG siRNA-transfected osteoblasts, that were implemented in murine calvarial critical size defect, accelerated bone regeneration as compared to control osteoblasts (Wan et al, 2007). Similarly, CHRD knockdown by siRNA accelerates the differentiation of MSC towards the osteoblastic lineage and leads to increased deposition of minerals in vitro (Kwong et al, 2008).…”

NVP-BEZ235, a dual pan class I PI3 kinase and mTOR inhibitor, promotes osteogenic differentiation in human mesenchymal stromal cells

“…BEZ235 also upregulates the expression of osteogenic growth factors such as BMP2, BMP6, BMP7, TGFB1, and TGFB2, all of which are known to be important inducers of RUNX2 expression, OB maturation, and mineral formation. The expression of Noggin, a potent BMP antagonist that inhibits osteogenesis in vitro and is associated with decreased bone formation in vivo, (49,50) also was strongly upregulated by BEZ235. In light of the strong pro-osteogenic response observed in these cells, this finding may appear somewhat contradictory.…”

Deleterious Effects of Freezing on Osteogenic Differentiation of Human Adipose-Derived Stromal Cells In Vitro and In Vivo

“…Eight years ago, Zuk et al described the ability of human adipose-derived stromal cells (hASCs) to differentiate along multiple mesodermal lineages [2,3]. Since that time, numerous studies from our laboratory and others have focused on the optimization of ASC osteogenic differentiation in vitro [4][5][6][7][8][9][10]. It is now clear that ASCs, whether derived from mouse or human origin, contribute to the osseous healing of surgically created skeletal defects [11,12].…”