Immunolocalization of BMPs, BMP antagonists, receptors, and effectors during fracture repair

Yu, Youcheng; Lieu, Shirley; Lu, Chuanyong; Miclau, Theodore; Marcucio, Ralph; Colnot, Céline

doi:10.1016/j.bone.2009.11.005

Cited by 98 publications

(91 citation statements)

References 57 publications

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“…Furthermore, it was shown that activation of the Bone morphogenetic protein (BMP) and Wingless-related (Wnt) signalling was crucial for the osteogenic capacity of the construct (Eyckmans et al, 2010). This is of specific interest since these pathways reflect the key growth factors during limb formation as well as normal fracture healing where they recruit/trigger periosteal cells to aid the fracture healing (Ai-Aql et al, 2008;Barnes et al, 1999;Cho et al, 2002;Yu et al, 2010). Nevertheless, bone formation in these constructs is a slow process and only limited amount of bone and marrow formation have been obtained until today.…”

Section: Introductionmentioning

confidence: 99%

The combined mechanism of bone morphogenetic protein- and calcium phosphate-induced skeletal tissue formation by human periosteum derived cells

Bolander

Ji²,

Geris

et al. 2016

eCM

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When combining osteogenic progenitor cells such as human periosteum derived cells (hPDCs) with osteoconductive biomaterials like calcium phosphate (CaP)-scaffolds, in vivo bone formation can be achieved. This process is dependent on the early activation of Bone morphogenetic protein (BMP)-signalling. However, the bone forming process is slow and routinely only a limited amount of bone and bone marrow is formed. Therefore, we hypothesised that a robust clinically relevant outcome could be achieved by adding more physiological levels of potent BMP-ligands to these cell-and CaP-based constructs.For this, hPDCs were characterised for their responsiveness to BMP-ligands upon in vitro 2D stimulation. BMP-2, -4, -6 and -9 robustly induced osteochondrogenic differentiation. Subsequently, these ligands were coated onto clinically approved CaP-scaffolds, BioOss ® and CopiOs ® , followed by hPDC-seeding. Protein lysates and conditioned media were investigated for activation of BMP signalling pathways. Upon in vivo implantation, the most abundant bone formation was found in BMP-2 and BMP-6-coated scaffolds. Implanted cells actively contributed to the newly formed bone. Remnants of cartilage could be observed in BMP-coated CopiOs ® -constructs.Computational analysis displayed that the type of BMPligand as well as the CaP-scaffold affects skeletal tissue formation, observed in a qualitative as well as quantitative manner. Furthermore, the in vitro mechanism appears to predict the in vivo outcome. This study presents further evidence for the potential of BMP-technology in the development of clinically relevant cell-based constructs for bone regenerative strategies.

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Section: Introductionmentioning

confidence: 99%

The combined mechanism of bone morphogenetic protein- and calcium phosphate-induced skeletal tissue formation by human periosteum derived cells

Bolander

Ji²,

Geris

et al. 2016

eCM

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“…Macrophage-colony stimulating factor (M-CSF), which is known to target mainly macrophages (33), is expressed in the fractured bone, peaking during inflammatory phase then again when remodelling phase starts (34) indicating an involvement of the macrophages during all phases of the repair. Macrophages and platelets produce bone morphogenetic proteins (BMPs), which contribute in organising the shape of the different tissues particularly bone and cartilage (35). BMPs are known to stimulate the proliferation of MSCs and enhance their osteogenic differentiation (36).…”

Section: Macrophages and Monocytesmentioning

confidence: 99%

“…The chronic inflammation and pathological bone formation are associated with dysregulation of BMPs and their inhibitors (35). The gene expression of BMP antagonists (noggin and follistatin) and certain MMPs, MMP-7 and MMP-12 are higher in non-union tissues compared to that in normal healing callus (196).…”

Section: Cytokinesmentioning

confidence: 99%

Interactions Between Multipotential Stromal Cells (MSCs) and Immune Cells During Bone Healing

El-Jawhari

Jones

McGonagle

et al. 2016

Recent Advances in Stem Cells

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Abstract:The physiological process of bone healing takes place in three sequential stages: inflammation, repair and remodelling. Multipotential stromal cells (MSCs) are the key progenitor cells for osteoblasts and chondrocytes and are also imbued with immunomodulatory capabilities.Although MSCs are well known to be involved in osteogenesis during the later stages of repair, their role during the inflammatory phase and precise interactions with immune cells remain poorly understood. This chapter describes the current knowledge on cellular interactions during the bone repair as well as cytokines and growth factors mediating these processes. The roles of emerging innate immune cell populations, innate lymphoid cells are also discussed.Based on this current knowledge, we conclude that in addition to their differentiation during later bone repair stages, MSCs are likely to have a substantial involvement in the initial stage of bone healing by controlling the fate of inflammation. An improved understanding of complex cell interactions during bone repair has broad implications on optimising the treatment of the fracture complications including non-union.

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“…Multiple BMPs are considered to have a crucial signalling role in chemotactic proliferation and differentiation of osteoprogenitor cells, thereby inducing bone formation. It has been reported that BMPs play a central role in the regulation of the three major stages of fracture healing (inflammation response, chondrogenic phase, and osteogenic phase); however, the molecular mechanisms of action are still being investigated [7,8]. Currently, there are two commercially available BMPs, recombinant human rh BMP-2 and rhBMP-7.…”

Section: Introductionmentioning

confidence: 99%

Clinical application of bone morphogenetic proteins for bone healing: a systematic review

Krishnakumar

Roffi

Reale

et al. 2017

International Orthopaedics (SICOT)

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Purpose This paper documents the existing evidence on bone morphogenetic proteins (BMPs) use for the treatment of bone fractures, non-union, and osteonecrosis, through a review of the clinical literature, underlying potential and limitations in terms of cost effectiveness and risk of complications. Methods A systematic review was performed on the PubMed database using the following string: (bone morphogenetic proteins OR BMPs) and (bone repair OR bone regeneration) including papers from 2000 to 2016. The search focused on clinical trials dealing with BMPs application to favor bone regeneration in bone fractures, non-union, and osteonecrosis, in English language, with level of evidence I, II, III, and IV. Relevant data (type of study, number of patients, BMPs delivery material, dose, site, follow-up, outcome, and adverse events) were extracted and analyzed. Results Forty-four articles met the inclusion criteria: 10 randomized controlled trials (RCTs), 7 comparative studies, 18 case series, and 9 case reports. rhBMP-2 was documented mainly for the treatment of fractures, and rhBMP-7 mainly for non-unions and osteonecrosis. Mixed results were found among RCTs and comparative papers: 11 reported positive results for BMPs augmentation, 3 obtained no significant effects, and 2 showed negative results. The only study comparing the two BMPs showed a better outcome with rhBMP-2 for non-union treatment. Conclusion Clinical evidence on BMPs use for the treatment of fractures, non-union, and osteonecrosis is still controversial, with the few available reports being mainly of low quality. While positive findings have been described in many studies, mixed results are still present in the literature in terms of efficacy and adverse events. The difficulties in drawing clear conclusions are also due to the studies heterogeneity, mainly in terms of different BMPs applied, with different concomitant treatments for each bone pathology. Therefore, further research with well-designed studies is needed in order to understand the real potential of this biological approach to favour bone healing.

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Immunolocalization of BMPs, BMP antagonists, receptors, and effectors during fracture repair

Cited by 98 publications

References 57 publications

The combined mechanism of bone morphogenetic protein- and calcium phosphate-induced skeletal tissue formation by human periosteum derived cells

The combined mechanism of bone morphogenetic protein- and calcium phosphate-induced skeletal tissue formation by human periosteum derived cells

Interactions Between Multipotential Stromal Cells (MSCs) and Immune Cells During Bone Healing

Clinical application of bone morphogenetic proteins for bone healing: a systematic review

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