Evidence map›Paper›PMID 26723577›Full record

ArticleBone2016

Combination therapy with BMP-2 and a systemic RANKL inhibitor enhances bone healing in a mouse critical-sized femoral defect.

Sofia Bougioukli, Ashish Jain, Osamu Sugiyama, Brian A Tinsley, Amy H Tang, Matthew H Tan, Douglas J Adams, Paul J Kostenuik, Jay R Lieberman

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Bone, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
29citing papers in PubMed, 1 pooled it
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

29 citing papers in PubMed, 1 synthesis or guideline pooled it.

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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

9 authors.

Sofia BougioukliDepartment of Orthopaedic Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
Ashish JainDepartment of Orthopaedic Surgery, UConn Musculoskeletal Institute, University of Connecticut Health, Farmington, CT, USA.
Osamu SugiyamaDepartment of Orthopaedic Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
Brian A TinsleyDepartment of Orthopaedic Surgery, UConn Musculoskeletal Institute, University of Connecticut Health, Farmington, CT, USA.
Amy H TangDepartment of Orthopaedic Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
Matthew H TanDepartment of Orthopaedic Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
Douglas J AdamsDepartment of Orthopaedic Surgery, UConn Musculoskeletal Institute, University of Connecticut Health, Farmington, CT, USA.
Paul J KostenuikPhylon Pharma Services, Newbury Park, CA, USA; Department of Periodontics and Oral Medicine, School of Dentistry, University of Michigan, Ann Arbor, MI, USA.
Jay R LiebermanDepartment of Orthopaedic Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. Electronic address: Jay.Lieberman@med.usc.edu.

Funding

The Use of Regional Gene Delivery to Heal Critical Sized Bone DefectsR01AR057076 · NIAMS · UNIVERSITY OF SOUTHERN CALIFORNIA · PI LIEBERMAN, JAY R. · 2010 to 2021
$3.9M
NIAMS NIH HHS R01 AR057076NIAMS NIH HHS R01AR057076-05
6 · The paper itself

Abstract

Recombinant human BMP-2 (rhBMP-2) is a potent osteoinductive agent, but has been associated not only with bone formation, but also osteoclastogenesis and bone resorption. Osteoprotegerin (OPG) is a RANKL inhibitor that blocks differentiation and function of osteoclasts. We hypothesized that the combination of local BMP-2 (recombinant protein or a product of gene therapy) plus systemic OPG-Fc is more effective than BMP-2 alone in promoting bone repair. To test this hypothesis we used a mouse critical-sized femoral defect model. Col2.3eGFP (osteoblastic marker) male mice were treated with rhBMP-2 (group I), rhBMP-2 and systemic OPG (group II), rhBMP-2 and delayed administration of OPG (group III), mouse BM cells transduced with a lentiviral vector containing the BMP-2 gene (LV-BMP-2; group IV), LV-BMP-2 and systemic OPG (group V), a carrier alone (group VI) and administration of OPG alone (group VII). All bone defects treated with BMP-2 (alone or combined with OPG) healed, whereas minimal bone formation was noted in animals treated with the carrier alone or OPG alone. MicroCT analysis showed that bone volume (BV) in rhBMP-2+OPG and LV-BMP-2+OPG groups was significantly higher compared to rhBMP-2 alone (p<0.01) and LV-BMP-2 alone (p<0.001). Similar results were observed in histomorphometry, with rhBMP-2 alone defects exhibiting significantly lower bone area (B.Ar) compared to rhBMP-2+OPG defects (p<0.005) and LV-BMP-2 defects having a significantly lower B.Ar compared to all BMP-2+OPG treated groups (p≤0.01). TRAP staining demonstrated a major osteoclast response in the groups that did not receive OPG (rhBMP-2, LV-BMP-2 and sponge alone) beginning as early as 7days post-operatively. In conclusion, we demonstrated that locally delivered BMP-2 (recombinant protein or gene therapy) in combination with systemically administered OPG improved bone healing compared to BMP-2 alone in a mouse critical-sized bone defect. These data indicate that osteoclasts can diminish healing responses to BMP-2 and that RANKL inhibition may thus accentuate BMP-2 efficacy.

Indexed as

Acid PhosphataseAnimalsBone Morphogenetic Protein 2Cell CountDrug Therapy, CombinationFemurFrozen SectionsHumansIsoenzymesLentivirusMaleMice, Inbred C57BLOsteoclastsOsteogenesisOsteoprotegerinRANK LigandAcid PhosphataseBone Morphogenetic Protein 2IsoenzymesOsteoprotegerinRANK Ligandrecombinant human bone morphogenetic protein-2Recombinant ProteinsTartrate-Resistant Acid PhosphataseTransforming Growth Factor betaAntiresorptivesBMPBone healingBone histomorphometryOsteoclasts

Identifiers

PMID26723577
PMCPMC4903101

What OpenQuestion holds

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Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.