Could the use of bone morphogenetic proteins in fracture healing do more harm than good to our patients?

Delimar, Domagoj; Smoljanović, Tomislav; Bojanić, Ivan

doi:10.1007/s00264-011-1397-1

Cited by 6 publications

(3 citation statements)

References 7 publications

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“…Clinical trials conducted using BMP-2 and BMP-7 to enhance bone repair showed that the method is not cost effective [9] – [11] . A recent review of 11 randomized controlled trials and 4 economical evaluations of BMPs for fracture repair concluded that only one study showed a difference in fracture healing between the BMP treated and control groups, but there was some suggestion that no second intervention was needed in the groups treated with BMP [10] .…”

Section: Introductionmentioning

confidence: 99%

BMP-Non-Responsive Sca1+CD73+CD44+ Mouse Bone Marrow Derived Osteoprogenitor Cells Respond to Combination of VEGF and BMP-6 to Display Enhanced Osteoblastic Differentiation and Ectopic Bone Formation

Madhu

Dighe

et al. 2014

PLoS ONE

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Clinical trials on fracture repair have challenged the effectiveness of bone morphogenetic proteins (BMPs) but suggest that delivery of mesenchymal stem cells (MSCs) might be beneficial. It has also been reported that BMPs could not increase mineralization in several MSCs populations, which adds ambiguity to the use of BMPs. However, an exogenous supply of MSCs combined with vascular endothelial growth factor (VEGF) and BMPs is reported to synergistically enhance fracture repair in animal models. To elucidate the mechanism of this synergy, we investigated the osteoblastic differentiation of cloned mouse bone marrow derived MSCs (D1 cells) in vitro in response to human recombinant proteins of VEGF, BMPs (-2, -4, -6, -9) and the combination of VEGF with BMP-6 (most potent BMP). We further investigated ectopic bone formation induced by MSCs pre-conditioned with VEGF, BMP-6 or both. No significant increase in mineralization, phosphorylation of Smads 1/5/8 and expression of the ALP, COL1A1 and osterix genes was observed upon addition of VEGF or BMPs alone to the cells in culture. The lack of CD105, Alk1 and Alk6 expression in D1 cells correlated with poor response to BMPs indicating that a greater care in the selection of MSCs is necessary. Interestingly, the combination of VEGF and BMP-6 significantly increased the expression of ALP, COL1A1 and osterix genes and D1 cells pre-conditioned with VEGF and BMP-6 induced greater bone formation in vivo than the non-conditioned control cells or the cells pre-conditioned with either VEGF or BMP-6 alone. This enhanced bone formation by MSCs correlated with higher CADM1 expression and OPG/RANKL ratio in the implants. Thus, combined action of VEGF and BMP on MSCs enhances osteoblastic differentiation of MSCs and increases their bone forming ability, which cannot be achieved through use of BMPs alone. This strategy can be effectively used for bone repair.

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Section: Introductionmentioning

confidence: 99%

BMP-Non-Responsive Sca1+CD73+CD44+ Mouse Bone Marrow Derived Osteoprogenitor Cells Respond to Combination of VEGF and BMP-6 to Display Enhanced Osteoblastic Differentiation and Ectopic Bone Formation

Madhu

Dighe

et al. 2014

PLoS ONE

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“…Current treatment options for high-risk fractures rely on autografts, allografts, synthetic bone graft substitutes, and FDAapproved bone morphogenetic protein-2 (BMP-2) based products. Severe shortages of autografts and allografts, donor site morbidity associated with autograft use, risk of disease transmission through allografts, lack of osteoinductive potential of synthetic grafts, and the requirement of very high doses of BMP-2 which can lead to undesirable side effects, necessitate further research on existing bone repair strategies (3)(4)(5)(6)(7)(8).…”

Section: Introductionmentioning

confidence: 99%

“…Decades of research has provided useful insights on the BMP signaling pathway and how activation of the BMP pathway induces differentiation of stem cells (9,10). However, BMP therapy still remains controversial (6)(7)(8). Adverse side effects arising from usage of high-dose BMP therapies have been reportedthese include swelling, postoperative inflammation, ectopic bone formation, osteoclast-mediated bone resorption, and unwanted adipogenesis (11).…”

Section: Introductionmentioning

confidence: 99%

BMP-6 promotes type 2 immune response during enhancement of rat mandibular bone defect healing

McColl

Chen²,

Solga³

et al. 2023

Front. Immunol.

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IntroductionBone morphogenetic proteins (BMPs) are used as key therapeutic agents for the treatment of difficult fractures. While their effects on osteoprogenitors are known, little is known about their effects on the immune system.MethodsWe used permutations of BMP-6 (B), vascular endothelial growth factor (V), and Hedgehog signaling pathway activator smoothened agonist (S), to treat a rat mandibular defect and investigated healing outcomes at week 8, in correlation with the cellular landscape of the immune cells in the fracture callus at week 2.ResultsMaximum recruitment of immune cells to the fracture callus is known to occur at week 2. While the control, S, V, and VS groups remained as nonunions at week 8; all BMP-6 containing groups - B, BV, BS and BVS, showed near-complete to complete healing. This healing pattern was strongly associated with significantly higher ratios of CD4 T (CD45+CD3+CD4+) to putative CD8 T cells (CD45+CD3+CD4-), in groups treated with any permutation of BMP-6. Although, the numbers of putative M1 macrophages (CD45+CD3-CD11b/c+CD38high) were significantly lower in BMP-6 containing groups in comparison with S and VS groups, percentages of putative - Th1 cells or M1 macrophages (CD45+CD4+IFN-γ+) and putative – NK, NKT or cytotoxic CD8T cells (CD45+CD4-IFN-γ+) were similar in control and all treatment groups. Further interrogation revealed that the BMP-6 treatment promoted type 2 immune response by significantly increasing the numbers of CD45+CD3-CD11b/c+CD38low putative M2 macrophages, putative - Th2 cells or M2 macrophages (CD45+CD4+IL-4+) cells and putative – mast cells, eosinophils or basophils (CD45+CD4-IL-4+ cells). CD45- non-haematopoietic fractions of cells which encompass all known osteoprogenitor stem cells populations, were similar in control and treatment groups.DiscussionThis study uncovers previously unidentified regulatory functions of BMP-6 and shows that BMP-6 enhances fracture healing by not only acting on osteoprogenitor stem cells but also by promoting type 2 immune response.

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Bone morphogenetic protein and orthopaedic surgery: Can we legitimate its off-label use?

Courvoisier

Sailhan

Laffenêtre

et al. 2014

International Orthopaedics (SICOT)

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Could the use of bone morphogenetic proteins in fracture healing do more harm than good to our patients?

Cited by 6 publications

References 7 publications

BMP-Non-Responsive Sca1+CD73+CD44+ Mouse Bone Marrow Derived Osteoprogenitor Cells Respond to Combination of VEGF and BMP-6 to Display Enhanced Osteoblastic Differentiation and Ectopic Bone Formation

BMP-Non-Responsive Sca1+CD73+CD44+ Mouse Bone Marrow Derived Osteoprogenitor Cells Respond to Combination of VEGF and BMP-6 to Display Enhanced Osteoblastic Differentiation and Ectopic Bone Formation

BMP-6 promotes type 2 immune response during enhancement of rat mandibular bone defect healing

Bone morphogenetic protein and orthopaedic surgery: Can we legitimate its off-label use?

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