Exaggerated inflammatory environment decreases BMP-2/ACS-induced ectopic bone mass in a rat model: implications for clinical use of BMP-2 R.-L. Huang,

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Exaggerated inflammatory environment decreases BMP-2/ACS-induced ectopic bone mass in a rat model: implications for clinical use of BMP-2 R.-L. Huang, Y. Yuan, J. Tu, G.-M. Zou, Q. Li Osteoarthritis and Cartilage Volume 22, Issue 8, Pages 1186-1196 (August 2014) DOI: 10.1016/j.joca.2014.06.017 Copyright © 2014 Osteoarthritis Research Society International Terms and Conditions

Fig. 1 Experimental protocol of this study. (A) Time course of the experimental protocol with times of LPS injections, BMP-2/ACS transplantation and sacrifice. (B) Experimental grouping and related experimental examination of this study. Osteoarthritis and Cartilage 2014 22, 1186-1196DOI: (10.1016/j.joca.2014.06.017) Copyright © 2014 Osteoarthritis Research Society International Terms and Conditions

Fig. 2 The elevation of exogenous cytokines BMP-2 and the expression profile of pro-inflammatory cytokines and anti-inflammatory cytokines in blood serum after BMP-2/ACS implantation. (A) Changes in body weight observed during the experimental period, as displayed by days 32 after BMP-2/ACS implantation (ANOVA test). (B–D) The blood serum specimens were collected at days −3, −2, 0, 2, 4, 7, 10, 13, 16, and 18; changes in the serum levels of TNF-α (B), IL-6 (C), and IL-1β (D) after LPS injections and BMP-2/ACS implantation during the experimental period (ANOVA test: P < 0.01 at days 0, 2, 4, and 7). (E) Fold changes of BMP-2, pro-inflammatory cytokines (IL-1α, IL-1β, IL-2, IL-6, IL-12p70, IFN-γ, GM-CSF, TNF-α), and anti-inflammatory cytokines (IL-4, IL-5, IL-10, IL-13) at days 0 and days 4 after implantation of BMP-2/ACS, compared with the serum from sham-operated rats (ANOVA test: P < 0.01). Data shown are means ± 95% CI (n = 10 per time point in the LPS-injected group and the saline-injected group, n = 5 per time point in the sham-operated group). Osteoarthritis and Cartilage 2014 22, 1186-1196DOI: (10.1016/j.joca.2014.06.017) Copyright © 2014 Osteoarthritis Research Society International Terms and Conditions

Fig. 3 LPS injections and BMP-2/ACS implantation triggered significant inflammatory infiltration surrounding ASC implants. Microscopic findings showed the inflammatory zone in H&E stained specimens from LPS-injected rats and saline-injected rats, harvested at 3 days (A) and 8 days after BMP-2/ACS implantation (B). The right panels showed the merged images of implants and the left panels showed the large images of implants (×100 magnification) (n = 6 per time point and group). Osteoarthritis and Cartilage 2014 22, 1186-1196DOI: (10.1016/j.joca.2014.06.017) Copyright © 2014 Osteoarthritis Research Society International Terms and Conditions

Fig. 4 Inflammatory environment decreased BMP-2-induced bone mass. (A) Gross view of BMP-2/ACS implant specimens from LPS-injected rats and saline-injected rats, harvested at 4 weeks and 8 weeks after implantation, scale bar = 1 mm. (B) Representative μCT, H&E staining, and VG staining images of BMP-2/ACS implants at 8 weeks from LPS-injected and saline-injected groups, scale bar = 1 mm, ×200 magnification. (C–H) TbTh (C), TbN (D), TbSp (E), BV (F), BMC (G), and BMD (H) of the newly formed bone nodules, measured by μCT. Data shown are means ± 95% CI (NB, new bone; ST, soft tissue; MT, mesenchymal tissue; Student's t test, n = 10 per time point and group). Osteoarthritis and Cartilage 2014 22, 1186-1196DOI: (10.1016/j.joca.2014.06.017) Copyright © 2014 Osteoarthritis Research Society International Terms and Conditions

Fig. 5 Exaggerated inflammatory environment changed expression of bone turnover markers. (A) Immunohistochemical staining of OCN in BMP-2/ACS implants from LPS-injected rats and saline-injected rats at 8 weeks. (B) Quantitation analysis of OCN expression in ×200 magnification. (C) TRAP staining of osteoclasts in BMP-2/ACS implants at 8 weeks in ×400 magnification. (D) Number of TRAP-positive cells per field of tissue in ×400 magnification. (E and F) Expression of OCN as a bone formation-related marker at mRNA level in implants and protein level in serum at 4 weeks, mRNA level normalized vs GAPDH. (G) Expression of Runx2 as a bone formation-related marker at protein level in serum at 4 weeks. (H) Secretion of TRAcP-5b as an osteoclast-related marker in serum in serum at 4 weeks. (I) Secretion of CTX-1 as a bone resorption-related marker in serum at 4 weeks. (J and K) Expression of RANKL (J) and OPG (K) in mRNA levels as bone resorption-related markers in implants at 4 weeks, normalized vs GAPDH. (L) RANKL/OPG ratio. Data shown are means ± 95% CI (NB, new bone; MT, mesenchymal tissue; OC, osteoclast; Student's t test, n = 10 per time point and group for tissue specimens, and n = 5 per time point and group for serum specimens). Osteoarthritis and Cartilage 2014 22, 1186-1196DOI: (10.1016/j.joca.2014.06.017) Copyright © 2014 Osteoarthritis Research Society International Terms and Conditions

Fig. 6 TNF-α and IL-1β, but not IL-6, attenuated BMP-2-induced osteoblastic differentiation of BMSCs. (A and B) BMSCs were treated with BMP-2 in the presence or absence of TNF-α, IL-6, and IL-1β respectively, ALP staining assay of ALPase activity on day 7 (A) and Alizarin red staining assay of calcium deposition on day 21 (B). (C) BMSCs were treated with BMP-2 in the presence or absence of TNF-α, IL-6, and IL-1β respectively in a dose-dependent experiment. Quantification assay of ALPase activity, normalized with total protein and compared with the saline-treated well. (D) Quantitative analysis of Alizarin red staining, compared with the saline-treated wells. (E–G) BMSCs were treated with BMP-2 in the presence or absence of TNF-α, IL-6, and IL-1β respectively for 48 h, real-time PCR and relative quantification of COL1A1 (E), OCN (F), and OPN (G), normalized vs GAPDH. Data shown are means ± 95% CI (Student's t test, n = 4 per group). Osteoarthritis and Cartilage 2014 22, 1186-1196DOI: (10.1016/j.joca.2014.06.017) Copyright © 2014 Osteoarthritis Research Society International Terms and Conditions

Fig. 7 Cartoon describing the possible mechanism for inflammatory environment decreasing BMP-2/ACS–induced ectopic bone mass. In this study, LPS injections and BMP-2/ACS implantation trigger an exaggerated inflammatory environment, which characterized by secretion of inflammatory cytokines and infiltration of inflammatory cells. Then, the exaggerated inflammatory environment inhibits BMP-2/ACS-induced osteoblastic differentiation of stem cells, and subsequently suppressed BMP-2/ACS-induced bone formation. However, the exaggerated inflammatory environment also activates osteoclastic-related bone resorption in this model. Taken together, the exaggerated inflammatory environment decreases BMP-2/ACS-induced bone mass through inhibition of osteoblastic-related bone formation and activation of osteoclastic-related bone resorption. Osteoarthritis and Cartilage 2014 22, 1186-1196DOI: (10.1016/j.joca.2014.06.017) Copyright © 2014 Osteoarthritis Research Society International Terms and Conditions