Characterizing the BMP pathway in a wild type mouse model of distraction osteogenesis

Haque, Tasima; Hamade, Fares; Alam, Norine; Kotsiopriftis, Maria; Lauzier, Dominique; St‐Arnaud, René; Hamdy, Reggie C.

doi:10.1016/j.bone.2008.01.028

Cited by 55 publications

(50 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Thus, in order to improve spinal fusion surgery, it is important to investigate the role of BMP antagonists that are likely produced by IVD cells and might regulate bone formation and differentiation potential of mesenchymal stem cells to osteoprogenitor cells. For instance, the expression of BMP antagonists is increased during fracture healing and distraction osteogenesis (Kloen et al, 2012;Dean et al, 2010;Haque et al, 2008). Similarly, it is hypothesised that BMP antagonists, such as NOG and DAN family, are responsible for the reported spinal nonunion, although recombinant human BMP2 (rhBMP2) and rhBMP7 are administered in the orthopaedics in very high doses (Govender et al, 2002;Friedlaender et al, 2001;Haid et al, 2004) probably to compensate for the inhibitory activity of the BMP antagonists.…”

Section: A Tekari Et Al the Role Of Bmp Signalling In Spinal Fusionmentioning

confidence: 99%

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

Tekari¹,

May²,

Frauchiger³

et al. 2017

eCM

View full text Add to dashboard Cite

Spinal fusion is hampered by the presence of remaining intervertebral disc (IVD) tissue and leads to spinal nonunion. While the exact mechanism remains unknown, we hypothesise that factors preventing disc ossification, such as antagonists of the bone morphogenetic proteins (BMP), could be responsible for this process.The objective of this study was to investigate spinal non-union using an in vitro human model with a focus on the BMP signalling components and to identify factors contributing to the incomplete and delayed ossification. Human bone marrow-derived mesenchymal stromal cells (MSC) were cocultured with IVD cells in the presence of L51P, a BMP2 variant with osteoinductive potential. The ossification of MSC was evaluated by quantitative reverse transcription polymerase chain reaction (qPCR), alkaline phosphatase (ALP) activity and alizarin red staining. Endogenous expression of major BMP antagonists, namely Gremlin (GREM1), Noggin (NOG) and Chordin (CHRD) was detected in IVD-derived cells, with abundance in nucleus pulposus cells. Osteogenesis of MSC was hindered by IVD cells as shown by reduced alizarin red staining, ALP activity and qPCR. L51P, added to the cocultures, restored mineralisation, blocking the activity of the BMP antagonists secreted by IVD cells.It is possible that the BMP antagonists secreted by IVD cells are responsible for spinal non-unions. The inhibition of BMP antagonists with L51P may result in an efficient and more physiological osteoinduction rather than delivery of exogenous osteogenic factors. Therefore, L51P might represent an attractive therapeutic candidate for bone healing.

show abstract

Section: A Tekari Et Al the Role Of Bmp Signalling In Spinal Fusionmentioning

confidence: 99%

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

Tekari¹,

May²,

Frauchiger³

et al. 2017

eCM

View full text Add to dashboard Cite

show abstract

“…PFF, pulsating fluid flow; Co, static control; PI, postincubation without PFF. *Significant effect of PFF, P \ 0.05 distraction osteogenesis; but BMP7 expression did not change during the distraction [38]. Mechanical tension during distraction osteogenesis in vivo increases BMP2 and BMP4, but not BMP7, gene expression [39].…”

Section: Discussionmentioning

confidence: 95%

Mechanical Loading Stimulates BMP7, But Not BMP2, Production by Osteocytes

et al. 2011

View full text Add to dashboard Cite

Bone mechanical adaptation is a cellular process that allows bones to adapt their mass and structure to mechanical loading. This process is governed by the osteocytes, which in response to mechanical loading produce signaling molecules that affect osteoblasts and osteoclasts. Bone morphogenic proteins (BMPs) are excellent candidates as signaling molecules, but it is unknown whether mechanically stimulated osteocytes affect bone adaptation through BMP production. Therefore, the aim of this study was to assess whether osteocytes produce BMPs in response to mechanical loading. In addition, since BMP7 has a vitamin D receptor (VDR) response element in the promoter region, we also investigated whether VDR is involved in the BMP7 response to mechanical loading. Human or VDR -/-mouse primary bone cells were submitted in vitro to 1 h pulsating fluid flow (PFF) and postincubated without PFF (PI) for 1-24 h, and gene and protein expression of BMP2 and BMP7 were quantified. In human bone cells, PFF did not change BMP2 gene expression, but it upregulated BMP7 gene expression by 4.4-to 5.6-fold at 1-3 h PI and stimulated BMP7 protein expression by 2.4-fold at 6 h PI. PFF did not stimulate BMP7 gene expression in VDR -/-mouse bone cells. These results show for the first time that mechanical loading upregulates BMP7, likely via the VDR, but not BMP2, gene and protein expression in osteocytes in vitro. Since BMP7 plays a major role in bone development and remodeling, these data might contribute to a better understanding of the mechanism leading to the mechanical adaptation of bone.Keywords Bone adaptation Á Bone morphogenic protein 2 Á Bone morphogenic protein 7 Á Osteocyte Á Mechanical loading Mechanical adaptation of bone is a cellular process that allows bones to adapt their mass and structure to their mechanical environment [1,2]. It is currently believed that this process of adaptation is governed by the osteocytes [3][4][5][6]. Osteocytes are terminally differentiated osteoblasts that become embedded deep within the mineralized bone matrix during bone formation. They are regularly distributed throughout the bone matrix and connected to each other by cytoplasmatic protrusions that run through the canaliculi [7]. This way the osteocytes form a unique dendritic network that enables contact not only with the bone surface but also with other cells [7]. When bones are loaded, the resulting deformation causes a flow of interstitial fluid through the lacunocanalicular network [8,9]. This flow of fluid results in mechanical stimulation of the osteocytes [6,8,9]. The mechanically stimulated osteocytes then produce signaling molecules that are potent regulators of the other types of bone cells, i.e., osteoblastsThe authors have stated that they have no conflict of interest.

show abstract

“…They also play a role in limb growth, possibly by triggering apoptosis in areas of developing limbs, sculpting them to the geometric needs (Merino, et al, 1999). receptors known as types I and II receptors (Haque, et al, 2008). BMP ligand must bind to a combination of two type I receptors and two type II receptors for signal transduction to be initiated ( Figure 6).…”

Section: Bone Morphogenetic Proteins and Bone Morphogenetic Protein Amentioning

confidence: 99%

“…These Smads, specifically Smads-1, -5, and -8 (receptor-regulated Smads), undergo chemical changes and then translocate into the nucleus, where the completed signaling complex either interacts with various factors or binds directly to DNA (Balemans & Van Hul, 2002;Haque, et al, 2008).…”

Section: Bone Morphogenetic Proteins and Bone Morphogenetic Protein Amentioning

confidence: 99%

“…This study will use the same protein chain (antibody, antibody, and enzyme) to try to indentify a cytokine in tissue rather than in serum. Such a process is not uncommon and has been used when trying to study BMPs or BMP antagonists in bone and other tissues, including cartilage, neural, lung and pancreatic tissue (Haque, et al, 2008;Haudenschild, et al, 2004;Koli, et al, 2006;Nakamura, et al, 2003;Tardif, et al, 2004). This difference should give us information on both location of the target cytokine and concentration, rather than just general concentration, as classic ELISA may be limited.…”

Section: Elisa and Immunohistochemical Stainingmentioning

confidence: 99%

See 1 more Smart Citation

An Investigative Study Into the Relationship of Bone Morphogenetic Protein Antagonist Expression and Osteocyte Density by Region and Quadrant

Mosher¹

View full text Add to dashboard Cite

The role of cytokines and cell behavior and viability with respect to bone remodeling and bone behavior is an exciting area of orthopedic research. The purpose of this study was to investigate the relationships between BMP antagonist expression and osteocyte density, lacunar densities and osteocyte viability in cortical bone. Samples of unloaded tibial bone obtained from six C57Bl/6 mice were immunohistochemically stained for gremlin and noggin expression and also underwent methyl green staining to determine osteocyte presence. Bone sections were divided into four quadrants (cranial, caudal, medial and lateral) and three regions (proximal, mid shaft and distal), followed by analysis across these quadrants and regions. The results showed matching regional differences in gremlin expression with regional variations in osteocyte density, lacunar density, and osteocyte viability. These variations were supported by positive correlations found via regression analysis. Regression analysis also showed marginal negative correlations between noggin expression and osteocyte density and osteocyte viability, supported by regional ANOVA results. Further research on loaded bone samples is needed if the relationship between these BMP antagonists and osteocyte densities are to be fully explained with respect to the bone remodeling process.

show abstract

Characterizing the BMP pathway in a wild type mouse model of distraction osteogenesis

Cited by 55 publications

References 34 publications

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

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

Mechanical Loading Stimulates BMP7, But Not BMP2, Production by Osteocytes

An Investigative Study Into the Relationship of Bone Morphogenetic Protein Antagonist Expression and Osteocyte Density by Region and Quadrant

Contact Info

Product

Resources

About