The Adjunctive Effect of a Binding Peptide on Bone Morphogenetic Protein Enhanced Bone Healing in a Rodent Model of Spinal Fusion

Alanay, Ahmet; Chen, Chi-Hui; Lee, Sang; Murray, Samuel S.; Brochmann, Elsa J.; Miyazaki, Masashi; Napoli, Antonia Passarelli di; Wang, Jeffrey C.

doi:10.1097/brs.0b013e31817e9dfd

Cited by 40 publications

(39 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A synthetic cyclic peptide (bone morphogenetic binding peptide, BBP) based on that sequence was shown to bind rhBMP-2 and enhance the bone forming activity of BMP-2. 6,7 On the other hand, full-length spp24 was shown to inhibit bone formation at ectopic sites, 8 in transgenic animals, 8 and in a rodent model of spinal fusion (manuscript in preparation). Thus, proteolytic processing converts spp24 from an inhibitor of bone formation 8 to an 18.5 kDa proosteogenic protein.…”

mentioning

confidence: 99%

Carboxy terminus of secreted phosphoprotein‐24 kDa (spp24) is essential for full inhibition of BMP‐2 activity

Brochmann

Simon²,

Jawien³

et al. 2010

Journal Orthopaedic Research

Self Cite

View full text Add to dashboard Cite

Secreted phosphoprotein-24 kDa (spp24) is a bone morphogenetic protein (BMP)-binding protein isolated from bone. It exists in a number of size forms and is hypothesized to function as a BMP latency protein and/or a ''slow release'' mechanism for BMPs involved in bone turnover and repair. We have examined the hypothesis that proteolytic modification of the C-terminus of spp24 affects its BMP-2-binding properties and bioactivity in the BMP-2-stimulated ectopic bone forming bioassay. Three different size forms of recombinant spp24 that correspond to predicted 18.1 kDa, 16.0 kDa, and 14.5 kDa proteolytic products were compared to full-length (fl) spp24. One of these forms (spp18.1) we hypothesize to be the protein which Urist initially, but apparently inaccurately, called ''BMP.'' Only full-length spp24 completely inhibited BMP-2-induced bone formation. The 18.1 kDa truncated isoform of spp24 which we hypothesize to be Urist's protein did not. The inhibitory capacity of the proteins was correlated with their kinetic constants, assessed by surface plasmon resonance. At the highest, inhibitory, dose of spp24 and its derivatives, k d (''stability'') best predicted the extent of ectopic bone formation whereas at the lowest dose, which was not inhibitory, k a (''recognition'') best predicted the extent of ectopic bone formation. We conclude that proteolytic processing of spp24 affects the interaction of this protein with BMP-2 and this affects the function of the protein. ß

show abstract

mentioning

confidence: 99%

Carboxy terminus of secreted phosphoprotein‐24 kDa (spp24) is essential for full inhibition of BMP‐2 activity

Brochmann

Simon²,

Jawien³

et al. 2010

Journal Orthopaedic Research

Self Cite

View full text Add to dashboard Cite

show abstract

“…Similar results were reported by previous studies. 9,10 However, when 1000 mg of BBP was combined with either 2 mg rhBMP-7 or 5 mg rhBMP-7, significant differences were seen in radiographic scores, manual palpation, and bone volume compared to 2 mg rhBMP-7 or 5 mg rhBMP-7 alone, suggesting that BBP itself does not have osteoinductive potential but can enhance the osteogenic activity of rhBMP-7. The estimated dissociation constant (K D ) between BBP and rhBMP-2 was 3 Â 10 À5 M, which was similar to that between BBP and TGF-B receptor II.…”

Section: Discussionmentioning

confidence: 99%

“…Alanay et al 9 conducted a study to evaluate the effects of two doses of BBP (500 and 1000 mg) on low dose (1 mg) rhBMP-2 in a rat spinal fusion model. Although combination of 1000 mg BBP and 1 mg rhBMP-2 can achieve earlier fusion by radiologic results when compared with administration of 1 mg rhBMP-2 alone, their final fusion rate did reach 100%.…”

Section: Discussionmentioning

confidence: 99%

“…These strategies include the use of delivery devices that allow better application of rhBMP-7 and obtain better retention at the surgery site, 7 the use of carriers that control the release of rhBMP-7, 8 and the use of a specific binding peptide that enhances the effect of rhBMP-2 in bone healing. 9 BMP binding peptide (BBP) was developed by Behnam et al 10 They isolated an 18.5 kDa fragment of the human bone matrix protein that has the chemical and physical properties of Urist's ''BMP.'' BBP enhanced rhBMP-2 induced ectopic bone formation in a mouse muscle pouch implantation model.…”

mentioning

confidence: 99%

“…10 Furthermore, this peptide also accelerated rhBMP-2 induced radiographic fusion in a rat spine model. 9 We hypothesized that BBP can be used to enhance bone healing of rhBMP-7 and that the effect is dose related. The purpose of our study was to combine rhBMP-7 with the BBP to determine if an increased efficacy of bone healing would occur when used in combination when implanted in a rat femoral defect model.…”

mentioning

confidence: 99%

See 2 more Smart Citations

Enhancement of recombinant human BMP‐7 bone formation with bmp binding peptide in a rodent femoral defect model

Liao

Tzeng

Keorochana

et al. 2010

Journal Orthopaedic Research

Self Cite

View full text Add to dashboard Cite

Bone morphogenetic binding peptide (BBP) is an 18.5 kDa fragment of a bone matrix protein peptide. A rat femoral defect model was used to test the effect of BBP combined with recombinant human bone morphogenetic protein-7 (rhBMP-7) to induced bone healing. Two doses of BBP (500 and 1000 mg) were tested with two doses of rhBMP-7 (2 and 5 mg), and the results were compared with a positive control (10 mg rhBMP-7). Bone healing was evaluated by radiology, manual palpation, microcomputed tomography, and histology. The high dose of 10 mg of rhBMP-7 resulted in a consistent 100% bone union rate and a mature histological appearance on histology, and was used as a positive control. When 1000 mg of BBP was combined with lower doses of BMP-7 (2 mg rhBMP-7 or 5 mg rhBMP-7) significant differences were seen in radiographic scores, manual palpation, and bone volume, when compared to 2 mg rhBMP-7 or 5 mg rhBMP-7 alone. The combination of 1000 mg of BBP and 5 mg rhBMP-7 also achieved 100% fusion rate, induced a larger amount of bone formation, and yielded similar maturity of bone marrow when compared with the high dosage 10 mg rhBMP-7 group. This study demonstrated that when combined together, BBP can enhance the bone healing of rhBMP-7. Improved healing imparted by the addition of BBP may result in lesser amounts of rhBMP-7 needed to achieve union in the clinical setting. ß

show abstract

A Novel Osteogenic Oxysterol Compound for Therapeutic Development to Promote Bone Growth: Activation of Hedgehog Signaling and Osteogenesis Through Smoothened Binding

Montgomery

Nargizyan

Meliton

et al. 2014

Journal of Bone and Mineral Research

View full text Add to dashboard Cite

Osteogenic factors are often used in orthopedics to promote bone growth, improve fracture healing, and induce spine fusion. Osteogenic oxysterols are naturally occurring molecules that were shown to induce osteogenic differentiation in vitro and promote spine fusion in vivo. The purpose of this study was to identify an osteogenic oxysterol more suitable for clinical development than those previously reported, and evaluate its ability to promote osteogenesis in vitro and spine fusion in rats in vivo. Among more than 100 oxysterol analogues synthesized, Oxy133 induced significant expression of osteogenic markers Runx2, osterix (OSX), alkaline phosphatase (ALP), bone sialoprotein (BSP), and osteocalcin (OCN) in C3H10T1/2 mouse embryonic fibroblasts and in M2-10B4 mouse marrow stromal cells. Oxy133-induced activation of an 8×-Gli luciferase reporter, its direct binding to Smoothened, and the inhibition of Oxy133-induced osteogenic effects by the Hedgehog (Hh) pathway inhibitor, cyclopamine, demonstrated the role of Hh pathway in mediating osteogenic responses to Oxy133. Oxy133 did not stimulate osteogenesis via BMP or Wnt signaling. Oxy133 induced the expression of OSX, BSP, and OCN and stimulated robust mineralization in primary human mesenchymal stem cells. In vivo, bilateral spine fusion occurred through endochondral ossification and was observed in animals treated with Oxy133 at the fusion site on xray after 4 weeks and confirmed with manual assessment, micro CT (μCT), and histology after 8 weeks, with equal efficiency to recombinant human bone morphogenetic protein-2 (rhBMP-2). Unlike rhBMP-2, Oxy133 did not induce adipogenesis in the fusion mass and resulted in denser bone evidenced by greater BV/TV ratio and smaller trabecular separation. Findings here suggest that Oxy133 has significant potential as an osteogenic molecule with greater ease of synthesis and improved time to fusion compared to previously studied oxysterols. Small molecule osteogenic oxysterols may serve as the next generation of bone anabolic agents for therapeutic development.

show abstract

The Adjunctive Effect of a Binding Peptide on Bone Morphogenetic Protein Enhanced Bone Healing in a Rodent Model of Spinal Fusion

Abstract: Specific growth factor binding agents, such as BBP, can be compounded into carriers used in fusion procedures to decrease the dosage of BMP and possibly decrease the side effects which are most likely dose-related. This may also decrease costs and improve clinical outcomes.

Cited by 40 publications

References 25 publications

Carboxy terminus of secreted phosphoprotein‐24 kDa (spp24) is essential for full inhibition of BMP‐2 activity

Carboxy terminus of secreted phosphoprotein‐24 kDa (spp24) is essential for full inhibition of BMP‐2 activity

Enhancement of recombinant human BMP‐7 bone formation with bmp binding peptide in a rodent femoral defect model

A Novel Osteogenic Oxysterol Compound for Therapeutic Development to Promote Bone Growth: Activation of Hedgehog Signaling and Osteogenesis Through Smoothened Binding

Contact Info

Product

Resources

About