The effect of NELL1 and bone morphogenetic protein-2 on calvarial bone regeneration.
OBJECTIVE
Most craniofacial birth defects contain skeletal components that require bone grafting. Although many growth factors have shown potential for use in bone regeneration, bone morphogenetic proteins (BMPs) are the most osteoinductive. However, supraphysiologic doses, high cost, and potential adverse effects stimulate clinicians and researchers to identify complementary molecules that allow a reduction in dose of BMP-2. Because NELL1 plays a key role as a regulator of craniofacial skeletal morphogenesis, especially in committed chondrogenic and osteogenic differentiation, and a previous synergistic mechanism has been identified, NELL1 is an ideal molecule for combination with BMP-2 in calvarial defect regeneration. We investigated the effect of NELL1 and BMP-2 on bone regeneration in vivo.


METHODS
BMP-2 doses of 589 and 1,178 ng were grafted into 5-mm critical-sized rat calvarial defects, as compared with 589 ng of NELL1 plus 589 ng of BMP-2 and 1,178 ng of NELL1 plus 1,178 ng of BMP-2, and bone regeneration was analyzed.


RESULTS
Live micro-computed tomography data showed increased bone formation throughout 4 to 8 weeks in all groups but a significant improvement when the lower doses of each molecule were combined. High-resolution micro-computed tomography and histology showed more mature and complete defect healing when the combination of NELL1 plus BMP-2 was compared with BMP-2 alone at lower doses.


CONCLUSIONS
The observed potential synergy has significant value in the future treatment of patients with craniofacial defects requiring extensive bone grafting that would normally entail extraoral autogenous bone grafts or doses of BMP-2 in milligrams.
Aghaloo
Tara
T
Dental and Craniofacial Research Institute and Section of Oral and Maxillofacial Surgery, School of Dentistry, University of California, Los Angeles, CA, USA.
Cowan
Catherine M
CM
Zhang
Xinli
X
Freymiller
Earl
E
Soo
Chia
C
Wu
Benjamin
B
Ting
Kang
K
Zhang
Zhiyuan
Z
D000818:Animals; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins / Q000008:administration & dosage / Q000494:pharmacology*; D001861:Bone Regeneration / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers; D004357:Drug Synergism; D006801:Humans; D019344:Lactic Acid; D008297:Male; D009419:Nerve Tissue Proteins / Q000008:administration & dosage / Q000494:pharmacology*; D011100:Polyglycolic Acid; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology*; D012886:Skull / Q000601:surgery; D016212:Transforming Growth Factor beta / Q000008:administration & dosage / Q000494:pharmacology*; D055114:X-Ray Microtomography
D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; D004337:Drug Carriers; C484480:Nell1 protein, rat; D009419:Nerve Tissue Proteins; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; C499469:recombinant human bone morphogenetic protein-2; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid