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. 2013 Feb;31(2):183-90.
doi: 10.1002/jor.22207. Epub 2012 Aug 15.

Impact of proteoglycan-4 and parathyroid hormone on articular cartilage

Chad M Novince  1 , Payam Entezami, Christopher G Wilson, Jason Wang, Seo Oh, Amy J Koh, Megan N Michalski, Benjamin P Sinder, Kenneth M Kozloff, Russell S Taichman, Laurie K McCauley
Affiliations

Impact of proteoglycan-4 and parathyroid hormone on articular cartilage

Chad M Novince et al. J Orthop Res. 2013 Feb.

Abstract

Proteoglycan-4 (Prg4) protects synovial joints from arthropathic changes by mechanisms that are incompletely understood. Parathyroid hormone (PTH), known for its anabolic actions in bone, increases Prg4 expression and has been reported to inhibit articular cartilage degeneration in arthropathic joints. To investigate the effect of Prg4 and PTH on articular cartilage, 16-week-old Prg4 mutant and wild-type mice were treated with intermittent PTH (1-34) or vehicle control daily for six weeks. Analyses included histology of the knee joint, micro-CT of the distal femur, and serum biochemical analysis of type II collagen fragments (CTX-II). Compared to wild-type littermates, Prg4 mutant mice had an acellular layer of material lining the surfaces of the articular cartilage and menisci, increased articular cartilage degradation, increased serum CTX-II concentrations, decreased articular chondrocyte apoptosis, increased synovium SDF-1 expression, and irregularly contoured subchondral bone. PTH-treated Prg4 mutant mice developed a secondary deposit overlaying the acellular layer of material lining the joint surfaces, but PTH-treatment did not alter signs of articular cartilage degeneration in Prg4 mutant mice. The increased joint SDF-1 levels and irregular subchondral bone found in Prg4 mutant mice introduce novel candidate mechanisms by which Prg4 protects articular cartilage.

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Conflict of interest statement

The authors had no competing interests.

Figures

Figure 1
Figure 1
Knee joint histopathology. 16-week-old Prg4 mutant (Prg4−/−) and wildtype (Prg4+/+) mice were administered intermittent PTH (1–34) (50μg/kg) or vehicle (VEH) (0.9% NaCl) control subcutaneous injection daily for 6 weeks. Knee joints were isolated from 22-week-old Prg4 mice for histological evaluation. Representative images of H&E stained sagittal knee sections (4X), with (inset) 20X image of the articular cartilage and posterior meniscus (black arrows indicate the acellular layer lining joint surfaces; yellow arrows indicate the secondary deposit associated with PTH-treatment).
Figure 2
Figure 2
Nature of the deposits overlaying the joint surfaces of Prg4 mutant mice. Representative images of meniscal surfaces (40X) in sagittal knee sections labeled with Safranin O-fast green stain, type 1 collagen IHC stain, type 2 collagen IHC stain (black arrows indicate labeling of the acellular layer lining joint surfaces; orange arrows indicate labeling of the secondary deposit associated with PTH-treatment).
Figure 3
Figure 3
Articular cartilage degradation. A: Representative images of Safranin O-fast green stained articular cartilage (40X) in sagittal knee sections. B: Bar graph represents the OARSI score (Grade X Stage) for the articular cartilage in the tibial plateau (n=8–10/gp). *p<0.01 vs. +/+ VEH; **p<0.01 vs. +/+ PTH. C: Bar graph represents serum C-terminal telopeptides of type II collagen (CTX-II) levels (n=8–10/gp). *p<0.01 vs. +/+ VEH; **p=0.08 vs. +/+ PTH.
Figure 4
Figure 4
Articular chondrocyte apoptosis. Representative images of TUNEL stained articular chondrocytes in sagittal knee sections: (A) 40X, (B) 100X (black arrows point to selected TUNEL+ chondrocytes). C: Bar graph represents the number of TUNEL+ chondrocytes per total chondrocytes (n≥5/gp). *p<0.01 vs. +/+ VEH; **p<0.001 vs. +/+ PTH. D: Bar graph represents the total number of chondrocytes per cartilage area (n≥5/gp).
Figure 5
Figure 5
Synovium SDF-1 expression. A: Representative images of stromal cell-derived factor-1 (SDF-1) immunofluorescence labeled synovium (60X) (SDF-1/Green and DAPI/Blue) (yellow arrows indicate SDF-1+ synovium) in sagittal knee sections. B: Representative images of SDF-1 immunohistochemistry labeled synovium (60X) (SDF-1/Brown) (black arrows indicate SDF-1+ synovial cells) in sagittal knee sections. C: Bar graph represents SDF-1 area/DAPI area in the synovium (n≥4/gp). *p<0.001 vs. +/+ VEH; **p<0.01 vs. +/+ PTH. D: Bar graph represents synovial cell SDF-1 intensity score (n=4/gp). *p<0.05 vs. +/+ VEH; **p<0.05 vs. +/+ PTH.
Figure 6
Figure 6
Subchondral bone morphology. Representative micro-CT images of the distal femur subchondral bone: (A) sagittal section view, (B) side view, (C) posterior view, (D) anterior view (yellow line indicates depth of patellar groove). E: Bar graph represents patellar groove depth (n=7–8/gp). *p<0.001 vs. +/+ VEH; **p<0.01 vs. +/+ PTH.
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