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Aging and disease    2019, Vol. 10 Issue (3) : 483-496     DOI: 10.14336/AD.2018.0616
Orginal Article |
Adipose-derived Stem Cells Attenuates Diabetic Osteoarthritis via Inhibition of Glycation-mediated Inflammatory Cascade
Navneet Kumar Dubey1,2, Hong-Jian Wei2,3,4, Sung-Hsun Yu2, David F. Williams5, Joseph R. Wang6, Yue-Hua Deng7, Feng-Chou Tsai8, Peter D. Wang4,9, Win-Ping Deng2,4,10,*
1Graduate Institute of Biomedical Materials and Tissue Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei, Taiwan
2Stem Cell Research Center, College of Oral Medicine, Taipei Medical University, Taipei, Taiwan
3School of Dental Technology, College of Oral Medicine, Taipei Medical University, Taipei, Taiwan
4School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei, Taiwan
5Wake Forest Institute of Regenerative Medicine, Winston-Salem, NC, USA
6Department of Periodontics, College of Dental Medicine, Columbia University, New York, USA
7Department of Life Science, Fu Jen Catholic University, New Taipei City, Taiwan
8Stem Cell Research Center, Cosmetic Clinic Group, Taipei, Taiwan
9Department of Dentistry, Taipei Medical University Hospital, Taipei, Taiwan
10Graduate Institute of Basic Medicine, Fu Jen Catholic University, New Taipei City, Taiwan
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Diabetes mellitus (DM) is well-known to exert complications such as retinopathy, cardiomyopathy and neuropathy. However, in recent years, an elevated osteoarthritis (OA) complaints among diabetics have been observed, portending the risk of diabetic OA. Since formation of advanced glycation end products (AGE) is believed to be the etiology of various diseases under hyperglycemic conditions, we firstly established that streptozotocin-induced DM could potentiate the development of OA in C57BL/6J mouse model, and further explored the intra-articularly administered adipose-derived stem cell (ADSC) therapy focusing on underlying AGE-associated mechanism. Our results demonstrated that hyperglycemic mice exhibited OA-like structural impairments including a proteoglycan loss and articular cartilage fibrillations in knee joint. Highly expressed levels of carboxymethyl lysine (CML), an AGE and their receptors (RAGE), which are hallmarks of hyperglycemic microenvironment were manifested. The elevated oxidative stress in diabetic OA knee-joint was revealed through increased levels of malondialdehyde (MDA). Further, oxidative stress-activated nuclear factor kappa B (NF-κB), the marker of proinflammatory signalling pathway was also accrued; and levels of matrix metalloproteinase-1 and 13 were upregulated. However, ADSC treatment attenuated all OA-like changes by 4 weeks, and dampened levels of CML, RAGE, MDA, NF-κB, MMP-1 and 13. These results suggest that during repair and regeneration, ADSCs inhibited glycation-mediated inflammatory cascade and rejuvenated cartilaginous tissue, thereby promoting knee-joint integrity in diabetic milieu.

Keywords Diabetes mellitus      osteoarthritis      articular cartilage      proteoglycans      advanced glycation end product      adipose-derived stem cells     
Corresponding Authors: Deng Win-Ping   
Issue Date: 30 March 2018
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Navneet Kumar Dubey
Hong-Jian Wei
Sung-Hsun Yu
David F. Williams
Joseph R. Wang
Yue-Hua Deng
Feng-Chou Tsai
Peter D. Wang
Win-Ping Deng
Cite this article:   
Navneet Kumar Dubey,Hong-Jian Wei,Sung-Hsun Yu, et al. Adipose-derived Stem Cells Attenuates Diabetic Osteoarthritis via Inhibition of Glycation-mediated Inflammatory Cascade[J]. Aging and disease, 2019, 10(3): 483-496.
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Figure 1.  Establishment of diabetes mellitus (DM)-induced osteoarthritis (OA) mice

(A) Schematic of experimental design representing establishment of streptozotocin (STZ)-induced DM. Mice at the age of 9 weeks were treated with single intraperitoneal injection of STZ (200mg/Kg body weight) or without STZ, designated as DM and control group, respectively. Measurement of fasting blood glucose (FBG) (B) and Body weight (C) of control and DM group mice after 4 weeks of STZ injection. (D) Representative gross appearance of control and DM mice showing distinct size differences. (E) Histologic assessment of OA characteristics in knee-joint of diabetic mice. The tissue sections were subjected to hematoxylin & eosin (H&E) staining, immunohistochemical staining of Col II (IHC Col II) and safranin O staining to determine the structural impairments, collagen and proteoglycan content, respectively in control and diabetes-induced osteoarthritis (DM-OA) group. The images in the upper panel are at lower magnification (scale bar: 500µm) in which the dotted rectangular boxed regions are represented as their respective images at higher magnification (scale bar: 200µm) in the lower panel. Data are shown as mean±SEM (Control, n=5; DM-OA, n=5). * p< 0.05 and *** p < 0.001.

Figure 2.  Characterization and corroboration of intra-articularly administered adipose-derived stem cells (ADSC) in knee joint of diabetic mice

ADSC were harvested from mice and characterized for presence of mesenchymal stem cell properties. (A) Representative photomicrographs of morphological characteristics of ADSC. Scale bars: 200 µm, (B) Immunophenotype assessment of ADSC via flow cytometry assay of percentage of positives mesenchymal stem cells markers (CD105 and CD90) and negative hematopoietic markers (CD34 and CD45). Representative photomicrographs of ADSC in (C) osteogenic medium (OS) and further stained with alizarin red (Ar) dye, and in (D) adipogenic medium (AD) which was further stained with oil red (Or) dye, and in (E) Chondrogenic medium (CH) which was further stained with alcian blue (Ab) dye. Scale bar: 200 μm. Determination of in vitro uptake of chloromethylbenzamido dialkylcarbocyanine (CM-DiL) in ADSC (Scale bar: 200µm) and their further confirmation through (F-a) fluorescence microscope, Scale bar: 200µm, and (F-b) Confocal laser scanning microscopy, Scale bar: 50µm. (G) Detection of intra-articularly transplanted ADSC. In vivo homing of injected CM-DiL-stained ADSC (thick yellow arrows) in synovial areas of knee-joint at week 2 and 4 (lower panel, f and h), respectively. Scale bars: 200µm.

Figure 3.  ADSC administration and assessment of histologic structural changes associated with OA

(A) Experimental protocol for ADSC therapy in STZ-mediated DM-induced OA mice. Following 2 weeks of lab adaptation, mice were rendered diabetic via administration of STZ (200mg/Kg body weight), and then blood glucose level was monitored till 4 weeks. After reaching >300mg/dl, 1×106 ADSC were intra-articularly injected. Thereafter, the improvement in OA status was assessed. (B) Representative images of hematoxylin and eosin (H&E) stained sections of mouse knee-joints injected with ADSC or PBS and control after 4 weeks. Rectangular boxed regions indicate the areas shown in higher magnification. The thickness of hyaline cartilage (HC) was indicated by blacked coloured double arrows. SBP represents the subchondral bone plate. Arrows in green, red and yellow colour indicated the cartilaginous lesions in femoral, tibial and meniscal regions. Bar: 500 μm (lower magnification, 10X), 200 μm (higher magnification, 20X). (C) Chondrocyte numbers in the femur (i) and tibia (ii) were quantified after 4 weeks of ADSC treatment. BG: blood glucose, BW: body weight. Data are shown as mean±SEM (Control, n=5; DM-OA+PBS, n=6; and DM-OA+ADSC, n=6). *p<0.05 and ** p<0.01.

Figure 4.  ADSC administration and assessment of proteoglycans (PG) and collagen content in knee-joint of diabetic mice

(A) Safranin-O/Fast Green staining for knee joint histological evaluation of PG in knee-joints injected with ADSC or PBS and control after 4 weeks. The upper panel of 3 images are at low magnification (500 μm) in which the dotted rectangular boxed regions are represented as their respective images (lower panel) at higher magnification (500 μm). Yellow and white arrows indicate accumulated proteoglycans in articular cartilage and meniscus respectively. (B) Severity of articular cartilage degradation was graded using OARSI scoring system. Data are shown as mean±SEM (Control, n=5; DM-OA+PBS, n=6; and DM-OA+ADSC, n=6). *** p<0.001. (C) Protein expression of biological markers of chondrogenic origin, including type II collagen and aggrecan (Col II and AGN).

Figure 5.  Effect of ADSC administration on expression of AGE-RAGE axis mediated activation of catabolic signalling pathways. (A) Immunohistochemistry was performed to assess the expression of CML as AGE (a-c), RAGE (d-f), MDA (g-i), NF-kB (j-l) MMP-1 (m-o) and MMP-13 (p-r) in diabetic knee-joints injected with ADSC or PBS and control after 4 weeks. The rectangular boxed regions in images at lower magnification (500 μm) are represented as their respective images at higher magnification (50 μm). Protein expressions (B) and their respective quantification (C) of CML, RAGE, NF-κB 65, MMP-1 and MMP-13 in control, DM-OA+PBS or DM-OA+ADSC group. *p<0.05, **p<0.01 and ***p<0.01. CML, carboxymethyl lysine; AGE, advanced glycation end product; RAGE, receptor for advanced glycation end products; NF-κB, nuclear factor kappa B; MMP, matrix metalloproteinase
Figure 6.  Schematic of possible mechanistic insight of therapeutic action by ADSC in osteoarthritic knee-joint of diabetic mice.
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