ISSLS PRIZE IN BASIC SCIENCE 2017: Intervertebral disc/bone marrow cross-talk with Modic changes

Abstract

Study design: Cross-sectional cohort analysis of patients with Modic Changes (MC).

Objective: Our goal was to characterize the molecular and cellular features of MC bone marrow and adjacent discs. We hypothesized that MC associate with biologic cross-talk between discs and bone marrow, the presence of which may have both diagnostic and therapeutic implications.

Background data: MC are vertebral bone marrow lesions that can be a diagnostic indicator for discogenic low back pain. Yet, the pathobiology of MC is largely unknown.

Methods: Patients with Modic type 1 or 2 changes (MC1, MC2) undergoing at least 2-level lumbar interbody fusion with one surgical level having MC and one without MC (control level). Two discs (MC, control) and two bone marrow aspirates (MC, control) were collected per patient. Marrow cellularity was analyzed using flow cytometry. Myelopoietic differentiation potential of bone marrow cells was quantified to gauge marrow function, as was the relative gene expression profiles of the marrow and disc cells. Disc/bone marrow cross-talk was assessed by comparing MC disc/bone marrow features relative to unaffected levels.

Results: Thirteen MC1 and eleven MC2 patients were included. We observed pro-osteoclastic changes in MC2 discs, an inflammatory dysmyelopoiesis with fibrogenic changes in MC1 and MC2 marrow, and up-regulation of neurotrophic receptors in MC1 and MC2 bone marrow and discs.

Conclusion: Our data reveal a fibrogenic and pro-inflammatory cross-talk between MC bone marrow and adjacent discs. This provides insight into the pain generator at MC levels and informs novel therapeutic targets for treatment of MC-associated LBP.

Keywords: Bone marrow; Cross-talk; Fibrosis; Inflammation; Modic change; Myelopoiesis; Neurotrophic; Osteoclastogenesis; Pain; Pathobiology.

Figures

Figure 1

Schematic drawing of tissue collection. Here, the upper level presents with Modic changes (asterisks). Four samples were collected per patient, two discs and two BM aspirates, one MC and one control tissue each. Disc tissue is collected with a bone rangeur (orange), bone marrow aspirates are taken with a Jamshidi needle (blue).

Figure 2

Genes with significant expression changes in Modic type 1 (MC1) and type 2 changes (MC2) in the (A) bone marrow and in the (B) adjacent intervertebral disc.

Figure 3

Changes in bone marrow cell populations in Modic type 1 (MC1) and type 2 (MC2) changes. (A) Metamyelocytes, mature polymorphonuclear cells (PMNs), and the ratio of metamyelocytes to mature PMNs. (B) Innate lymphoid cells (ILC), ILC type 1–3 (ILC1-3), and natural killer cells (NKC), (C) CD45-negative cells, and erythroblasts, (D) Differentiation potential of myeloid progenitor cells quantified as colony-forming units (CFUs) of nucleated cells. Changes relative to autologous control bone marrow are indicated. CFUs of multi-potential erythroid-macrophage-megakaryocyte progenitors (GEMM), granulocyte/macrophage progenitors (GM), granulocyte progenitors (G), macrophage progenitors (M), and of burst-forming unit erythroids (E) were analyzed.