title: Low-dose interleukin-1 partially counteracts osteogenic protein-1-induced proteoglycan synthesis by adult bovine intervertebral disk cells.
abstract: OBJECTIVE
  Low back pain associated with degenerative disk disease is a common clinical problem that has enormous socioeconomic impact in today's aging population. As an alternative to the surgical removal of the diseased intervertebral disk, the direct application of a purified growth factor into the intervertebral disk may provide physiatrists a valuable tool to halt or slow down disk degeneration. Our goal here is to determine if low levels of interleukin-1 (IL-1), a proinflammatory cytokine present in the degenerating disk, could interfere with the potentially beneficial effects of growth factors on proteoglycan synthesis. New knowledge gained from this study will prove useful in the development of new treatment modalities that take advantage of the stimulatory effects of growth factors such as osteogenic protein-1 (OP-1).
  
  
  METHODS
  This was an in vitro study of proteoglycan accumulation and synthesis by cells from the nucleus pulposus, inner annulus fibrosus, and outer annulus fibrosus in the bovine intervertebral disk.
  
  
  RESULTS
  In cells cultured with serum and no additional exogenous growth factor, treatment with low-dose IL-1 does not result in a significant decrease in proteoglycan synthesis. However, in the case of cells stimulated with OP-1, treatment with IL-1 resulted in a statistically significant decrease in sulfur-35-proteoglycan synthesis by cells derived from all three zones of the bovine intervertebral disk (nucleus pulposus, 60.3% [P < 0.0001]; inner annulus fibrosus, 18.4% [P = 0.0330]; outer annulus fibrosus, 12.3% [P = 0.0255]). Proteoglycan accumulation over the 12-day culture period also decreased significantly (nucleus pulposus, 26.8% [P < 0.0001]; inner annulus fibrosus, 15.8% [P = 0.0276]; outer annulus fibrosus, 16.8% [P = 0.0102]). It is worth noting that cells cultured in the presence of both OP-1 and IL-1 synthesized proteoglycan at a faster rate than cells cultured in the presence of IL-1 alone (nucleus pulposus, 58.5% [P < 0.0001]; inner annulus fibrosus, 39.7% [P = 0.0055]; outer annulus fibrosus, 45.1% [P = 0.0164]). Likewise, cells treated with OP-1 and IL-1 accumulated more proteoglycan in their newly formed matrix than cells cultured in the presence of IL-1 alone (nucleus pulposus, 65.3% [P < 0.0001]; inner annulus fibrosus, 60.5% [P = 0.0034]; outer annulus fibrosus, 19.4% (P = 0.0840]).
  
  
  CONCLUSIONS
  Intervertebral disk cells that are stimulated by the growth factor OP-1, to increase the rate at which they produce a proteoglycan-rich matrix become more susceptible to the inhibitory effects of the proinflammatory cytokine IL-1 on the rate of proteoglycan synthesis and accumulation in the matrix over time. This notwithstanding, IL-1 at the low dose used did not totally obliterate the stimulatory effects of OP-1 on matrix formation. Consequently, this growth factor may remain partially effective in stimulating disk repair in vivo even when proinflammatory cytokines such as IL-1 are present.
authors.affiliation: Department of Physical Medicine and Rehabilitation, Rush University Medical Center, Chicago, Illinois, USA.
authors.forename: Yejia
authors.initials: Y
authors.lastname: Zhang
authors.forename: Howard S
authors.initials: HS
authors.lastname: An
authors.forename: Marc
authors.initials: M
authors.lastname: Toofanfard
authors.forename: Zhen
authors.initials: Z
authors.lastname: Li
authors.forename: Gunnar B J
authors.initials: GB
authors.lastname: Andersson
authors.forename: Eugene J M A
authors.initials: EJ
authors.lastname: Thonar
mesh_terms: D000818:Animals; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins / Q000494:pharmacology*; D002417:Cattle; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D007375:Interleukin-1 / Q000494:pharmacology*; D007403:Intervertebral Disc / Q000166:cytology*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D011509:Proteoglycans / Q000096:biosynthesis* / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
chemical_list: D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins; D007375:Interleukin-1; D018696:Neuroprotective Agents; D011509:Proteoglycans; D016212:Transforming Growth Factor beta