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IGFBP-5 Metabolism Is Disrupted in the Rat Medial Meniscal Tear Model of Osteoarthritis.

Yates MP, Settle SL, Yocum SA, Aggarwal P, Vickery LE, Aguiar DJ, Skepner AP, Kellner D, Weinrich SL, Sverdrup FM - Cartilage (2010)

Bottom Line: This activity was stimulated by calcium and was sensitive to serine protease inhibitors as well as peptide PB-145.Inhibition of IGFBP-5 proteolysis protected cartilage from lesion development and enhanced cartilage turnover.These data are consistent with IGFBP-5 playing a positive role in anabolic IGF signaling in cartilage.

View Article: PubMed Central - PubMed

Affiliation: Pfizer Global Research and Development, Chesterfield, Missouri.

ABSTRACT
Insulin-like growth factor binding protein 5 (IGFBP-5) has been proposed to promote cartilage anabolism through insulin-like growth factor (IGF-1) signaling. A proteolytic activity towards IGFBP-5 has been detected in synovial fluids from human osteoarthritic (OA) joints. The purpose of this study was to determine if protease activity towards IGFBP-5 is present in the rat medial meniscal tear (MMT) model of OA and whether inhibition of this activity would alter disease progression. Sprague-Dawley rats were subject to MMT surgery. Synovial fluid lavages were assessed for the presence of IGFBP-5 proteolytic activity. Treatment animals received intra-articular injections of vehicle or protease inhibitor peptide PB-145. Cartilage lesions were monitored by India ink staining followed by macroscopic measurement of lesion width and depth. The MMT surgery induced a proteolytic activity towards IGFPB-5 that was detectable in joint fluid. This activity was stimulated by calcium and was sensitive to serine protease inhibitors as well as peptide PB-145. Significantly, intra-articular administration of PB-145 after surgery protected cartilage from lesion development. PB-145 treatment also resulted in an increase in cartilage turnover as evidenced by increases in serum levels of procollagen type II C-propeptide (CPII) as well as synovial fluid lavage levels of collagen type II neoepitope (TIINE). IGFBP-5 metabolism is disrupted in the rat MMT model of OA, potentially contributing to cartilage degradation. Inhibition of IGFBP-5 proteolysis protected cartilage from lesion development and enhanced cartilage turnover. These data are consistent with IGFBP-5 playing a positive role in anabolic IGF signaling in cartilage.

No MeSH data available.


Related in: MedlinePlus

Scoring of joints for cartilage lesion severity. (A) Scoring system. (B) Surface irregularity scores (*P < 0.05). (C) Staining intensity scores (*P < 0.05). (D) Total tibial degeneration scores (*P < 0.05). Total tibial score of a normal healthy joint is zero. Statistical analyses based on a 2-sided t test for independent samples.
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fig6-1947603509359189: Scoring of joints for cartilage lesion severity. (A) Scoring system. (B) Surface irregularity scores (*P < 0.05). (C) Staining intensity scores (*P < 0.05). (D) Total tibial degeneration scores (*P < 0.05). Total tibial score of a normal healthy joint is zero. Statistical analyses based on a 2-sided t test for independent samples.

Mentions: To quantify the severity of cartilage lesions, a scoring system was devised that included a measure to reflect the apparent thicker cartilage in PB-145–treated joints (see Methods for details). The tibial surface was first imaged horizontally, and the area of India ink staining was outlined manually for the total area of lesions. The depth of lesions was evaluated by physical probing. Because the total area of cartilage lesions was not necessarily decreased in PB-145 samples, a new measure designated “skyline” depth or concavity was generated from viewing the medial tibial plateau from the anterior to posterior direction. A line drawn from the highest point on the inside (nearest the cruciate ligaments) to the highest point on the outside of the tibial plateau represents zero concavity. From this line, a perpendicular line was drawn to the deepest part of the curve, which was recorded as the “skyline” depth in pixels (Fig. 5A). Representative skyline photographs from group 2 (vehicle) (Fig. 5B) and group 3 (PB-145 100 ug) (Fig. 5C) show the reduced skyline depth in PB-145–treated animals. The skyline data from all animals in groups 1 to 4 (Fig. 5D) indicate a dose response reduction in the depth of lesions with PB-145 treatment. In order to compare the combined data from all measurements, a total score was calculated that included multiplying the surface irregularity score by the area of India ink staining and then adding the staining intensity and “skyline” concavity scores (Fig. 6A). The surface irregularity score (Fig. 6B), staining intensity score (Fig. 6C), and the total tibial score (Fig. 6D) all indicate improvement of gross tibial cartilage morphology with PB-145 treatment compared to vehicle.


IGFBP-5 Metabolism Is Disrupted in the Rat Medial Meniscal Tear Model of Osteoarthritis.

Yates MP, Settle SL, Yocum SA, Aggarwal P, Vickery LE, Aguiar DJ, Skepner AP, Kellner D, Weinrich SL, Sverdrup FM - Cartilage (2010)

Scoring of joints for cartilage lesion severity. (A) Scoring system. (B) Surface irregularity scores (*P < 0.05). (C) Staining intensity scores (*P < 0.05). (D) Total tibial degeneration scores (*P < 0.05). Total tibial score of a normal healthy joint is zero. Statistical analyses based on a 2-sided t test for independent samples.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4440612&req=5

fig6-1947603509359189: Scoring of joints for cartilage lesion severity. (A) Scoring system. (B) Surface irregularity scores (*P < 0.05). (C) Staining intensity scores (*P < 0.05). (D) Total tibial degeneration scores (*P < 0.05). Total tibial score of a normal healthy joint is zero. Statistical analyses based on a 2-sided t test for independent samples.
Mentions: To quantify the severity of cartilage lesions, a scoring system was devised that included a measure to reflect the apparent thicker cartilage in PB-145–treated joints (see Methods for details). The tibial surface was first imaged horizontally, and the area of India ink staining was outlined manually for the total area of lesions. The depth of lesions was evaluated by physical probing. Because the total area of cartilage lesions was not necessarily decreased in PB-145 samples, a new measure designated “skyline” depth or concavity was generated from viewing the medial tibial plateau from the anterior to posterior direction. A line drawn from the highest point on the inside (nearest the cruciate ligaments) to the highest point on the outside of the tibial plateau represents zero concavity. From this line, a perpendicular line was drawn to the deepest part of the curve, which was recorded as the “skyline” depth in pixels (Fig. 5A). Representative skyline photographs from group 2 (vehicle) (Fig. 5B) and group 3 (PB-145 100 ug) (Fig. 5C) show the reduced skyline depth in PB-145–treated animals. The skyline data from all animals in groups 1 to 4 (Fig. 5D) indicate a dose response reduction in the depth of lesions with PB-145 treatment. In order to compare the combined data from all measurements, a total score was calculated that included multiplying the surface irregularity score by the area of India ink staining and then adding the staining intensity and “skyline” concavity scores (Fig. 6A). The surface irregularity score (Fig. 6B), staining intensity score (Fig. 6C), and the total tibial score (Fig. 6D) all indicate improvement of gross tibial cartilage morphology with PB-145 treatment compared to vehicle.

Bottom Line: This activity was stimulated by calcium and was sensitive to serine protease inhibitors as well as peptide PB-145.Inhibition of IGFBP-5 proteolysis protected cartilage from lesion development and enhanced cartilage turnover.These data are consistent with IGFBP-5 playing a positive role in anabolic IGF signaling in cartilage.

View Article: PubMed Central - PubMed

Affiliation: Pfizer Global Research and Development, Chesterfield, Missouri.

ABSTRACT
Insulin-like growth factor binding protein 5 (IGFBP-5) has been proposed to promote cartilage anabolism through insulin-like growth factor (IGF-1) signaling. A proteolytic activity towards IGFBP-5 has been detected in synovial fluids from human osteoarthritic (OA) joints. The purpose of this study was to determine if protease activity towards IGFBP-5 is present in the rat medial meniscal tear (MMT) model of OA and whether inhibition of this activity would alter disease progression. Sprague-Dawley rats were subject to MMT surgery. Synovial fluid lavages were assessed for the presence of IGFBP-5 proteolytic activity. Treatment animals received intra-articular injections of vehicle or protease inhibitor peptide PB-145. Cartilage lesions were monitored by India ink staining followed by macroscopic measurement of lesion width and depth. The MMT surgery induced a proteolytic activity towards IGFPB-5 that was detectable in joint fluid. This activity was stimulated by calcium and was sensitive to serine protease inhibitors as well as peptide PB-145. Significantly, intra-articular administration of PB-145 after surgery protected cartilage from lesion development. PB-145 treatment also resulted in an increase in cartilage turnover as evidenced by increases in serum levels of procollagen type II C-propeptide (CPII) as well as synovial fluid lavage levels of collagen type II neoepitope (TIINE). IGFBP-5 metabolism is disrupted in the rat MMT model of OA, potentially contributing to cartilage degradation. Inhibition of IGFBP-5 proteolysis protected cartilage from lesion development and enhanced cartilage turnover. These data are consistent with IGFBP-5 playing a positive role in anabolic IGF signaling in cartilage.

No MeSH data available.


Related in: MedlinePlus