Contributions
Abstract: EP1500
Type: Poster Sessions
Abstract Category: Pathology and pathogenesis of MS - Repairing mechanisms
Background: Neurogenesis and oligodendrogenesis in MS lesions are negligible, and it is assumed that anti- neurogenic factors suppress them. Bone morphogenetic proteins (BMPs) are known to promote astrogenesis, at the expense of NSCs acquisition of neuronal/ oligodendroglial phenotype. Coco is a secreted 25 kDa protein, a member of the Cerberus/Dan/Gremlin superfamily of BMP inhibitors. It is known to inhibit BMP2 and BMP4. We have previously reported that BMP2 levels are elevated in sera of RRMS patients.
Objective: To study Coco levels in the sera of RRMS patients and their biological significance in a bioassay.
Methods: Sera samples were collected from 41 untreated RRMS patients, 37 IFNβ treated RRMS patients, and 36 matched HC. Sera Coco levels were examined by ELISA. Dose response experiments of Coco on P19 cells differentiation into MAP2+ neurons was done in the presence of retinoic acid (RA) and BMP-2.
Results: Coco serum levels were significantly reduced in untreated RRMS patients, vs. matched HC (1219.7 ± 195.1 pg/ml vs. 1883.3 ± 243.2 pg/ml, respectively, p=0.03). Treatment with IFNβ did not affect Coco serum levels (1256.9 ± 256.2 pg/ml). Stimulation of P19 cells with 5x10-7M RA for 4 days triggered the emergence of MAP2+ cells on day 8 (66.6 ± 6.1% in response to RA vs. 3.2 ± 1.6% in response to no stimulation, p=0.001). Addition of 5 ng/ml rhBMP-2 significantly reduced the number of MAP-2+ cells (6.4% ± 2.6, p=0.01 vs. RA alone), whereas the addition of 500 ng/ml anti-BMP2/4 mAb reversed the effect of BMP2 on neurogenesis by inducing acquisition of the neuronal phenotype (49.4 ± 4.0%, p=0.004 vs. RA+BMP-2). Replacement of the anti- BMP2/4 Ab with 500 pg/ml Coco, or with 1200 pg/ml Coco, did not significantly induce neurogenesis (9.1 ± 1.8% and 21.4 ± 4.3%, respectively, p=0.43 and p=0.08 vs. RA+BMP2 alone). However, addition of 1800 pg/ml Coco significantly enhanced MAP2+ cells (51.9 ± 4.4%, p=0.004 vs. RA+BMP2 alone, and p=0.008 vs. RA+BMP2+1200 pg/ml Coco). Stimulation with 5000 pg/ml Coco did not further augment MAP2+ cells (55.3 ± 1.1%, p=0.49 vs. 1800pg/ml Coco).
Conclusions: Reduced Coco levels in the serum of RRMS patients, concomitant with elevated levels of BMP2, may contribute to the anti- neurogenic niche in MS lesions. The difference between Coco levels in the serum of RRMS patients and HC may have a biologic significance as was demonstrated in P19 model, suggesting an additional mechanism for neurogenesis failure in MS.
Disclosure: The study was partialy funded by Merck
Mausner-Fainberg K: nothing to disclose, Golan M: nothing to disclose, Ben Hamou M: nothing to disclose, Karni A: nothing to disclose
Abstract: EP1500
Type: Poster Sessions
Abstract Category: Pathology and pathogenesis of MS - Repairing mechanisms
Background: Neurogenesis and oligodendrogenesis in MS lesions are negligible, and it is assumed that anti- neurogenic factors suppress them. Bone morphogenetic proteins (BMPs) are known to promote astrogenesis, at the expense of NSCs acquisition of neuronal/ oligodendroglial phenotype. Coco is a secreted 25 kDa protein, a member of the Cerberus/Dan/Gremlin superfamily of BMP inhibitors. It is known to inhibit BMP2 and BMP4. We have previously reported that BMP2 levels are elevated in sera of RRMS patients.
Objective: To study Coco levels in the sera of RRMS patients and their biological significance in a bioassay.
Methods: Sera samples were collected from 41 untreated RRMS patients, 37 IFNβ treated RRMS patients, and 36 matched HC. Sera Coco levels were examined by ELISA. Dose response experiments of Coco on P19 cells differentiation into MAP2+ neurons was done in the presence of retinoic acid (RA) and BMP-2.
Results: Coco serum levels were significantly reduced in untreated RRMS patients, vs. matched HC (1219.7 ± 195.1 pg/ml vs. 1883.3 ± 243.2 pg/ml, respectively, p=0.03). Treatment with IFNβ did not affect Coco serum levels (1256.9 ± 256.2 pg/ml). Stimulation of P19 cells with 5x10-7M RA for 4 days triggered the emergence of MAP2+ cells on day 8 (66.6 ± 6.1% in response to RA vs. 3.2 ± 1.6% in response to no stimulation, p=0.001). Addition of 5 ng/ml rhBMP-2 significantly reduced the number of MAP-2+ cells (6.4% ± 2.6, p=0.01 vs. RA alone), whereas the addition of 500 ng/ml anti-BMP2/4 mAb reversed the effect of BMP2 on neurogenesis by inducing acquisition of the neuronal phenotype (49.4 ± 4.0%, p=0.004 vs. RA+BMP-2). Replacement of the anti- BMP2/4 Ab with 500 pg/ml Coco, or with 1200 pg/ml Coco, did not significantly induce neurogenesis (9.1 ± 1.8% and 21.4 ± 4.3%, respectively, p=0.43 and p=0.08 vs. RA+BMP2 alone). However, addition of 1800 pg/ml Coco significantly enhanced MAP2+ cells (51.9 ± 4.4%, p=0.004 vs. RA+BMP2 alone, and p=0.008 vs. RA+BMP2+1200 pg/ml Coco). Stimulation with 5000 pg/ml Coco did not further augment MAP2+ cells (55.3 ± 1.1%, p=0.49 vs. 1800pg/ml Coco).
Conclusions: Reduced Coco levels in the serum of RRMS patients, concomitant with elevated levels of BMP2, may contribute to the anti- neurogenic niche in MS lesions. The difference between Coco levels in the serum of RRMS patients and HC may have a biologic significance as was demonstrated in P19 model, suggesting an additional mechanism for neurogenesis failure in MS.
Disclosure: The study was partialy funded by Merck
Mausner-Fainberg K: nothing to disclose, Golan M: nothing to disclose, Ben Hamou M: nothing to disclose, Karni A: nothing to disclose