Role of C‐reactive protein in the bone marrow of Modic type 1 changes

Abstract

Modic type 1 changes (MC1) are vertebral bone marrow lesions and associate with low back pain. Increased serum C-reactive protein (CRP) has inconsistently been associated with MC1. We aimed to provide evidence for a role of CRP in the tissue pathophysiology of MC1 bone marrow. From thirteen MC1 patients undergoing spinal fusion at MC1 levels, vertebral bone marrow aspirates from MC1 and intra-patient control bone marrow were taken. Bone marrow CRP, IL-1, and IL-6 were measured with enzyme-linked immunosorbent assays; lactate dehydrogenase (LDH) was measured with a colorimetric assay. CRP, IL-1, and IL-6 were compared between MC1 and control bone marrow. Bone marrow CRP was correlated with blood CRP and with bone marrow IL-1, IL-6, and LDH. CRP expression by marrow cells was measured with PCR. Increased CRP in MC1 bone marrow (mean difference: +0.22 mg CRP/g protein, 95% CI [-0.04, 0.47], p=0.088) correlated with blood CRP (r=0.69, p=0.018), with bone marrow IL-1 (=0.52, p=0.029) and IL-6 (=0.51, p=0.031). Marrow cells did not express CRP. Increased LDH in MC1 bone marrow (143.1%, 95% CI [110.7%, 175.4%], p=0.014) indicated necrosis. A blood CRP threshold of 3.2 mg/L detected with 100% accuracy increased CRP in MC1 bone marrow. In conclusion, the association of CRP with inflammatory and necrotic changes in MC1 bone marrow provides evidence for a pathophysiological role of CRP in MC1 bone marrow.

The role of the complement system in disc degeneration and Modic changes

“…They found that increased CRP levels in MC BM correlated with blood CRP levels. 76 This supports previous reports of increased serum CRP in MC patients and pinpointed the MC lesion as the relevant area for elevated CRP levels. 77 CRP is an acute-phase protein, like SAP, also belonging to the pentraxin family of innate pattern recognition molecules.…”

“…A further study assessed MC BM aspirates from patients undergoing spinal fusion surgery. They found that increased CRP levels in MC BM correlated with blood CRP levels 76 . This supports previous reports of increased serum CRP in MC patients and pinpointed the MC lesion as the relevant area for elevated CRP levels 77 .…”

“…Endplate damage leads to necrotic cell death and necrosis in MC BM is evident by increased LDH. 68,76,82 CRP, which is increased in MC BM, might bind to exposed phosphocholine on damaged cell membranes of necrotic cells and potentially activates the complement system via C1q. 71 Necrotic cells also release intracellular components that can act as damage-associated molecular patterns (DAMPs) like high-mobility group box 1 (HMGB1), which could also initiate classical complement system activation in MC 83,84 Necrosis as a potential complement system activator in MC is supported by findings from osteoarthritis, a degenerative joint disease characterized by excessive breakdown of articular cartilage and increased chondrocyte death, where chondrocyte necrosis leads to complement activation.…”

“…Endplate damage leads to necrotic cell death and necrosis in MC BM is evident by increased LDH 68,76,82 . CRP, which is increased in MC BM, might bind to exposed phosphocholine on damaged cell membranes of necrotic cells and potentially activates the complement system via C1q 71 .…”

Cartilaginous endplates: A comprehensive review on a neglected structure in intervertebral disc research

“…Recent studies confirm the possibility that activated immune cells in MC1 bone marrow can lead to CEP damage 158 . Increased lactate dehydrogenase activity and increased concentration of C‐reactive protein and of complement factors in MC bone marrow indicate also a humoral immune response related to local tissue damage 125,159 . On a cellular level, CEP cells at MC levels express more tumor necrosis factor (TNF), a disintegrin and metalloproteinase with thrombospondin motifs‐5 (ADAMTS‐5), macrophage migration inhibitory factor (MIF), and its receptor CD74 124,160,161 .…”