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Lineage tracking of mesenchymal and endothelial progenitors in BMP-induced bone formation.

ABSTRACT: To better understand the relative contributions of mesenchymal and endothelial progenitor cells to rhBMP-2 induced bone formation, we examined the distribution of lineage-labeled cells in Tie2-Cre:Ai9 and ?SMA-creERT2:Col2.3-GFP:Ai9 reporter mice. Established orthopedic models of ectopic bone formation in the hind limb and spine fusion were employed. Tie2-lineage cells were found extensively in the ectopic bone and spine fusion masses, but co-staining was only seen with tartrate-resistant acid phosphatase (TRAP) activity (osteoclasts) and CD31 immunohistochemistry (vascular endothelial cells), and not alkaline phosphatase (AP) activity (osteoblasts). To further confirm the lack of a functional contribution of Tie2-lineage cells to BMP-induced bone, we developed conditional knockout mice where Tie2-lineage cells are rendered null for key bone transcription factor osterix (Tie2-cre:Osx(fx/fx) mice). Conditional knockout mice showed no difference in BMP-induced bone formation compared to littermate controls. Pulse labeling of mesenchymal cells with Tamoxifen in mice undergoing spine fusion revealed that ?SMA-lineage cells contributed to the osteoblastic lineage (Col2.3-GFP), but not to endothelial cells or osteoclast populations. These data indicate that the ?SMA+ and Tie2+ progenitor lineages make distinct cellular contributions to bone formation, angiogenesis, and resorption/remodeling.

SUBMITTER: Kolind M

PROVIDER: S-EPMC4844190 | biostudies-other | 2015 Dec

REPOSITORIES: biostudies-other

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Lineage tracking of mesenchymal and endothelial progenitors in BMP-induced bone formation.

Kolind Mille M Bobyn Justin D JD Matthews Brya G BG Mikulec Kathy K Aiken Alastair A Little David G DG Kalajzic Ivo I Schindeler Aaron A

Bone 20150702

To better understand the relative contributions of mesenchymal and endothelial progenitor cells to rhBMP-2 induced bone formation, we examined the distribution of lineage-labeled cells in Tie2-Cre:Ai9 and αSMA-creERT2:Col2.3-GFP:Ai9 reporter mice. Established orthopedic models of ectopic bone formation in the hind limb and spine fusion were employed. Tie2-lineage cells were found extensively in the ectopic bone and spine fusion masses, but co-staining was only seen with tartrate-resistant acid p ...[more]

PMID: 26141839

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Project description:Recombinant human bone morphogenic protein-2 (BMP-2)-loaded absorbable collagen sponges (ACS) have been successfully used to enhance bone formation and to induce spinal fusion in humans. However, side effects, such as soft tissue edema and inflammation, have been reported. NEMO binding domain peptide (NBD) inhibits activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-?B), a central regulator of immune response. In this study, we investigated NBD's potential to reduce BMP-2-induced soft tissue inflammation without affecting BMP-2-mediated spinal fusion in rat. For evaluation of soft tissue inflammation, ACS containing BMP-2, BMP-2+NBD, NBD, or ACS only were implanted into intramuscular paraspinal sites of 32 rats. At day 2 postsurgery, edema formation at the implant sites was assessed using magnetic resonance imaging. T2-weighted relaxation time (T2-RT) values were increased in the BMP-2 group compared with BMP-2+NBD, NBD, and ACS groups. No difference in T2-RT values was detected between BMP-2+NBD versus NBD and ACS controls. Postsacrifice, histological analysis of the implant-surrounding zones showed increased mononuclear cell infiltration in the BMP-2 group compared with BMP-2+NBD and controls. The presence of BMP-2 increased relative NF-?B binding and gene expression of inflammatory markers, interleukin (IL)1?, IL6, IL18, and chemokine ligand (CCL)2 and CCL3 compared with controls. In the BMP-2+NBD group, cytokine expression was blocked. No differences were found between BMP-2+NBD and control groups. For evaluation of spinal fusion, posterolateral intertransverse lumbar fusion procedures were performed on 16 rats. ACS were loaded with BMP-2 or BMP-2+NBD. After sacrifice at week 12, microcomputed tomographic assessment of the fusion site detected a higher bone volume and reduced trabecular spacing in the BMP-2+NBD group compared with BMP-2. Histological analysis did not show any differences in newly formed bone microarchitecture. In summary, addition of NBD to BMP-2-loaded ACS reduces BMP-2-induced soft tissue edema formation and mononuclear cell infiltration, diminishes NF-?B binding, and thus blocks transcription of NF-?B-regulated cytokines in rat. Furthermore, NBD stimulates bone formation in BMP-2-mediated spinal fusion, possibly through crosstalk of the NF-?B pathway with other pathways. The results of this study might provide the basis to develop new therapeutic bone grafting approaches with combinatory administration of BMP-2 and NBD for spinal fusion.

Dataset Information

Lineage tracking of mesenchymal and endothelial progenitors in BMP-induced bone formation.

Publications

Lineage tracking of mesenchymal and endothelial progenitors in BMP-induced bone formation.

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