The Effect of NELL1 and Bone Morphogenetic Protein-2 on Calvarial Bone Regeneration

Abstract

Purpose 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. Materials and 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. Conclusion 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.

BMP2-Induced Inflammation Can Be Suppressed by the Osteoinductive Growth Factor NELL-1

“…37 In addition, NELL-1 has been described to have combinatorial or synergistic bone-forming effects when combined with BMP2 in various in vivo models, including a nude mouse intramuscular model, rat calvarial defect model, and a rabbit maxillary sinus floor elevation model. [43][44][45] Recently, our laboratory performed preliminary studies geared toward bone regeneration, in which to our surprise we found that NELL-1 also significantly attenuated BMP2-induced inflammation. In this study, we formally investigated whether the growth factor NELL-1 could reduce the inflammation frequently encountered with BMP2 treatment.…”

Realizing the potential of gene-based molecular therapies in bone repair

“…Although BMP-2 and BMP-7 may represent the initial choice for gene delivery, more potent proteins were recently identified that may allow for a greater response with lower amounts. (129) Because of the crucial role of vascularization in new bone formation, angiogenic proteins can enhance bone formation. (130) In particular, VEGF (131) and bFGF (132,133) have been shown to be beneficial on their own for osteogenesis and in combinations with BMPs.…”

“…(146,147) NEL-like molecule-1 (Nell-1) is another molecule under investigation for its osteogenic properties in repair of large segmental defects. (148)(149)(150) Nell-1 was shown to be as effective as BMP-2 in repair of critical-size defect (151) and also works synergistically with BMPs (129) that are endogenously expressed at the defect site. These proteins and, their combinations, are expected to provide further leads in aiding or even replacing BMPs in functional bone regeneration.…”

Pharmacokinetics and osteogenic potential of PEGylated NELL-1 in vivo after systemic administration

“…Specifically, NELL-1 is a 700kDa protein recognized as a potent pro-osteogenic cytokine and was most often studied for its local bone-forming effects [17][18][19][20][21][22][23][24]. NELL-1 has been reported to induce robust osseous healing of critical-sized rat femoral segmental and calvarial defects [17,25,26], and also to promote lumbar spinal fusion in rats, sheep [21][22][23], and non-human primates. Additionally, NELL-1 has been identified not only to demonstrate anti-osteoclastic effects both in vitro and in vivo [19], but also to suppress adipogenesis [27].…”