Prevention of disc degeneration with growth factors

Abstract

Clinically, a large number of patients have persistent low back pain attributable to intervertebral disc (IVD) degeneration. After the concept of biologically regenerating the degenerated IVD using growth factor injection was first proposed in early 1990, the advancement of molecular technology to produce recombinant proteins, including growth factors, on an industrial scale accelerated research in this field. The purpose of this review is to summarize the most recent findings of the in vitro and in vivo effects of growth factors on the IVD and, further, to discuss the limitations of growth factor therapy and its clinical implications. In vitro data showed that stimulation of matrix synthesis by growth factors alters the balance of homeostasis by shifting cellular metabolism to the anabolic state. In vivo data using small animals has shown the possibility of using growth factors as a "structural modifying therapy". Based on in vitro and in vivo data previously reported, the clinical application of growth factors by direct injection of protein into the nucleus pulposus or anulus fibrosus was shown to be feasible as a new therapeutic intervention for treatment of disc degeneration. Stimulation of the biological repair process will create a new category of therapy to treat disc degeneration, where no active treatment currently exists, between conservative therapies and more aggressive therapies such as fusion or disc replacement. However, it should be noted that there are several important factors to be taken into consideration. In a relatively advanced degenerative condition, the supply of nutrients is disturbed and stimulation of cellular activity by growth factors may result in an increased demand for nutrients, eventually inducing an adverse event. Further investigations of the optimal environment for growth factor stimulation should be pursued. Growth factor therapy, which has experimental evidence supporting it to be a "structural modifying therapy", may not be a "symptom modifying therapy" that is able to resolve the symptoms associated with pathologic changes. Therefore, further studies on the effect of growth factor therapy on pain are essential to shed light on its therapeutic usefulness for degenerative disc disease.

Fig. 1

Effect of recombinant human rhOP-1 treatment on collagen synthesis by NP and AF cells cultured in alginate beads (Reprinted from Masuda K et al. (2003) J Orthop Res 21:922–930, with permission from Elsevier). After 7 days in culture, NP and AF cells were cultured for an additional 72 h in DMEM/F12+10% FBS containing various concentrations of rhOP-1. Newly synthesized PGs, formed during the last 4 h of culture in the presence of [³⁵S]-sulfate, were quantified. In both NP and AF cultures, significant, dose-dependent, increases in the rate of synthesis per μg DNA were observed after the addition of rhOP-1 to the medium (a). Newly synthesized collagens, formed during the last 16 h of culture in the presence of L- [2,3,4,5-³H]-proline, were quantified. rhOP-1 stimulated collagen synthesis by both NP cells and AF cells in a dose-dependent manner (b). CM cell-associated matrix, FBS fetal bovine serum, FRM further-removed matrix, NaCl sodium chloride extract, SDS SDS extract

Fig. 2

Effect of recombinant human growth and differentiation factor-5 (rhGDF-5) on proteoglycan (PG) synthesis, (top), collagen synthesis (middle), and PG content (bottom) by bovine NP and AF cells in vitro (From: Chujo T et al (2006) Trans Orthop Res Soc 14, with permission. Spine: in print). Top: Cells were cultured in DMEM/F12+10% FBS in the presence or absence of 100 and 200 ng/ml of rhGDF-5 for 21 days and then PG synthesis was assessed. NP cells treated with rhGDF-5 showed a greater response than AF cells. A dose-dependent effect of rhGDF-5 was observed in NP cells only at day 21. Middle: The rate of collagen synthesis was also significantly higher in the rhGDF-5 groups (100 and 200 ng/ml) than in the control group at all time points in both cell types. Bottom: On days 7, 14, and 21, the PG content in alginate beads was measured. rhGDF-5, at both concentrations, stimulated PG accumulation in beads containing NP cells at all time points and in beads containing AF cells at the 14- and 21-day time points

Fig. 3

Effect of PRP treatment on proteoglycan (PG) synthesis by NP and AF cells cultured in alginate beads (From: Akeda K et al. (2006) Spine, 31:959–966, with permission). During the last 4 h of the 72-h treatment period, the cells were radiolabeled with ³⁵S-sulfate (20 μCi/ml) and the amount of radiolabeled ³⁵S-PGs in the cell-associated matrix (CM) extract, the further-removed matrix (FRM) fraction and the media were quantified. PG synthesis in the PRP-treated NP and AF cells was significantly higher than that in the platelet-poor plasma (PPP)- and FBS-treated cells. SFM: serum free media

Fig. 4

Changes in intervertebral disc height index (DHI) after anular puncture and OP-1 injection (with permission, Masuda K et al. (2006) Spine, 31:742–754). The percent DHI (%DHI = [postoperative DHI/preoperative DHI] × 100) was measured at each time point to quantify changes in disc height. By 4 weeks after the OP-1 injection, the mean %DHI of injected discs in the OP-1 group was significantly higher than that in the lactose control group (P<0.001, repeated ANOVA). This significant difference in mean %DHI was maintained during the follow-up period (P<0.001)

Fig. 5

Changes in intervertebral disc height index (DHI) after anular puncture and rhGDF-5 injections (Reprinted from: Chujo T et al. (2005) Spine J. S: S145 with permission from Elsevier, Spine in print). By 4 weeks after the rhGDF-5 injection, the mean %DHI of injected discs in the rhGDF-5 group (100 μg) was significantly higher than in the PBS group (P<0.05). Six weeks after the injection of rhGDF-5, the %DHI was significantly higher, at doses of 1 and 100 μg, in the rhGDF-5 group when compared to the PBS group (control versus rhGDF-5 1 and 100 μg; P<0.01). The effect of a single injection of rhGDF-5 continued to be significant throughout the study