BMP7 enhances the effect of BMSCs on extracellular matrix remodeling in a rabbit model of intervertebral disc degeneration

Abstract

Intervertebral discs (IVDs) provide stability and flexibility to the spinal column; however, IVDs, and in particular the nucleus pulposus (NP), undergo a degenerative process characterized by changes in the disc extracellular matrix (ECM), decreased cell viability, and reduced synthesis of proteoglycan and type II collagen. Here, we investigated the efficacy and feasibility of stem cell therapy using bone marrow mesenchymal stem cells (BMSCs) over-expressing bone morphogenetic protein 7 (BMP7) to promote ECM remodeling of degenerated IVDs. Lentivirus-mediated BMP7 over-expression induced differentiation of BMSCs into an NP phenotype, as indicated by expression of the NP markers collagen type II, aggrecan, SOX9 and keratins 8 and 19, increased the content of glycosaminoglycan, and up-regulated b-1,3-glucuronosyl transferase 1, a regulator of chondroitin sulfate synthesis in NP cells. These effects were suppressed by Smad1 silencing, indicating that the effect of BMP7 on ECM remodeling was mediated by the Smad pathway. In vivo analysis in a rabbit model of disc degeneration showed that implantation of BMSCs over-expressing BMP7 promoted cell differentiation and proliferation in the NP, as well as their own survival, and these effects were mediated by the Smad pathway. The results of the present study indicate the beneficial effects of BMP7 on restoring ECM homeostasis in NP cells, and suggest potential strategies for improving cell therapy for the treatment of disc diseases.

Bone Morphogenetic Proteins for Nucleus Pulposus Regeneration

“…To remedy the low amount of cells present, a combination of BMPs and MSCs could further augment IVD regeneration. In this scenario, BMPs are expected to both stimulate the resident NPs to proliferate and produce the matrix and facilitate MSCs to enter the chondrogenic lineage [34].…”

Improving Cell Therapy Survival and Anabolism in Harsh Musculoskeletal Disease Environments

“…Delivery of BMP-7 expressing cells has been performed for DD models as BMP-7 exerts chondrogenic effects and is known to stimulate anabolic effects in disc cells too. 121,122 These studies demonstrated improved morphology and tissue content measured months after delivery in rodent and rabbit DD models, indicating potential longer term effects with this approach. 121,122 Other lesser known factors have also been utilized that induce desired musculoskeletal phenotypes.…”

“…121,122 These studies demonstrated improved morphology and tissue content measured months after delivery in rodent and rabbit DD models, indicating potential longer term effects with this approach. 121,122 Other lesser known factors have also been utilized that induce desired musculoskeletal phenotypes. Overexpression of NELL-1 has been utilized to improve repair of osteochondral defects as NELL-1 is known to induce stem cells down an osteochondral lineage.…”

Use of Allogeneic Hypoxic Mesenchymal Stem Cells For Treating Disc Degeneration in Rabbits

“…Consequently, BMP‐7 injection has been utilized to treat IVD degeneration in various animal models, including rabbits and canines . Xu et al observed that the implantation of MSCs overexpressing BMP‐7 promotes cell differentiation and proliferation in the nucleus pulposus. In the current study, we showed that injecting hypoxic MSCs resulted in the upregulation of disc BMP‐7 expression as compared to that in discs injected with normoxic MSCs.…”