Abstract
Poor solute transport through the cartilage endplate (CEP) impairs disc nutrition and could be a key factor that limits the success of intradiscal biologic therapies. Here we demonstrate that treating the CEP with matrix metalloproteinase-8 (MMP-8) reduces the matrix constituents that impede solute uptake and thereby improves nutrient diffusion. Human CEP tissues harvested from four fresh cadaveric lumbar spines (age range: 38–66 years old) were treated with MMP-8. Treatment caused a dose-dependent reduction in sGAG, localized reductions to the amount of collagen, and alterations to collagen structure. These matrix modifications corresponded with 16–24% increases in the uptake of a small solute (376 Da). Interestingly, the effects of MMP-8 treatment depended on the extent of non-enzymatic glycation: treated CEPs with high concentrations of advanced glycation end products (AGEs) exhibited the lowest uptake compared to treated CEPs with low concentrations of AGEs. Moreover, AGE concentrations were donor-specific, and the donor tissues with the highest AGE concentrations appeared to have lower uptake than would be expected based on the initial amounts of collagen and sGAG. Finally, increasing solute uptake in the CEP improved cell viability inside diffusion chambers, which supports the nutritional relevance of enhancing the transport properties of the CEP. Taken together, our results provide new insights and in vitro proof-of-concept for a treatment approach that could improve disc nutrition for biologic therapy: specifically, matrix reduction by MMP-8 can enhance solute uptake and nutrient diffusion through the CEP, and AGE concentration appears to be an important, patient-specific factor that influences the efficacy of this approach.
Highlights
Low back pain is the most common and most costly musculoskeletal condition [1], and is significantly associated with intervertebral disc degeneration [2]
matrix metalloproteinase-8 (MMP-8) displayed a dose-dependent reduction in total Sulfated glycosaminoglycan (sGAG) from the cartilage endplate (CEP) (Fig 2A), with the highest dose releasing over 20% of sGAG
matrix metalloproteinases (MMPs)-8 treatment at 2 U/mL significantly increased the viable distance in the diffusion chambers by an average 13%, indicating improved nutrient diffusion through the CEP between the culture medium outside the chambers and the nucleus pulposus (NP) cells inside the chambers. These results show that MMP-8 treatment improves the uptake of a small solute into cadaveric human CEP tissues (p = 0.0004 to 0.06)
Summary
Low back pain is the most common and most costly musculoskeletal condition [1], and is significantly associated with intervertebral disc degeneration [2]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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