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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

India ink staining of rat tibial plateaus 4 weeks after medial meniscal tear (MMT) surgery. Representative photographs are shown for each group and depict either the entire tibial plateau (group 1) or medial tibial plateaus (groups 2-4). (A) Group 1, no intra-articular treatment. (B) Group 2, intra-articular injections of vehicle. (C) Group 3, intra-articular injections of 100 ug PB-145. (D) Group 4, intra-articular injections of 500 ug PB-145. Injections were given twice weekly for 3 weeks starting 1 week after MMT surgery.
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fig4-1947603509359189: India ink staining of rat tibial plateaus 4 weeks after medial meniscal tear (MMT) surgery. Representative photographs are shown for each group and depict either the entire tibial plateau (group 1) or medial tibial plateaus (groups 2-4). (A) Group 1, no intra-articular treatment. (B) Group 2, intra-articular injections of vehicle. (C) Group 3, intra-articular injections of 100 ug PB-145. (D) Group 4, intra-articular injections of 500 ug PB-145. Injections were given twice weekly for 3 weeks starting 1 week after MMT surgery.

Mentions: We next determined if PB-145 would protect cartilage from lesion development in the rat MMT model of OA. Beginning 1 week after MMT, rats were given twice-weekly intra-articular injections of PB-145 or saline as a vehicle control. An additional group of animals did not receive intra-articular injections (no treatment controls). Figure 4A shows India ink staining of an entire tibial plateau 4 weeks after MMT with no treatment. The darkest areas of staining on the medial tibial plateau (left side) indicate deep focal lesions that span nearly the full depth of the cartilage to the underlying subchondral bone. The lighter stained areas represent less severe cartilage degeneration. Note the smooth cartilage and lack of any staining on the lateral tibial plateau (right side), which is typical of this model. Figure 4B depicts the medial aspects of the tibial plateaus from 2 representative animals in the vehicle (saline) treated group. Again, deep focal lesions with an extended area of staining and fibrillation are present. Treatment with PB-145 reduced the depth and severity of lesions. Figure 4C shows medial tibial plateaus from the low-dose PB-145 group (100 ug/injection). Focal lesions are still present, but there are no full-thickness lesions, and the fibrillated area is shallower in depth, and staining with India ink is less intense. Figure 4D shows medial tibial plateaus from the high-dose PB-145 group (500 ug/injection). Instead of focal lesions, there is a thick layer of cartilage with a rough, slightly fibrillated surface and faint India ink staining.


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)

India ink staining of rat tibial plateaus 4 weeks after medial meniscal tear (MMT) surgery. Representative photographs are shown for each group and depict either the entire tibial plateau (group 1) or medial tibial plateaus (groups 2-4). (A) Group 1, no intra-articular treatment. (B) Group 2, intra-articular injections of vehicle. (C) Group 3, intra-articular injections of 100 ug PB-145. (D) Group 4, intra-articular injections of 500 ug PB-145. Injections were given twice weekly for 3 weeks starting 1 week after MMT surgery.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4440612&req=5

fig4-1947603509359189: India ink staining of rat tibial plateaus 4 weeks after medial meniscal tear (MMT) surgery. Representative photographs are shown for each group and depict either the entire tibial plateau (group 1) or medial tibial plateaus (groups 2-4). (A) Group 1, no intra-articular treatment. (B) Group 2, intra-articular injections of vehicle. (C) Group 3, intra-articular injections of 100 ug PB-145. (D) Group 4, intra-articular injections of 500 ug PB-145. Injections were given twice weekly for 3 weeks starting 1 week after MMT surgery.
Mentions: We next determined if PB-145 would protect cartilage from lesion development in the rat MMT model of OA. Beginning 1 week after MMT, rats were given twice-weekly intra-articular injections of PB-145 or saline as a vehicle control. An additional group of animals did not receive intra-articular injections (no treatment controls). Figure 4A shows India ink staining of an entire tibial plateau 4 weeks after MMT with no treatment. The darkest areas of staining on the medial tibial plateau (left side) indicate deep focal lesions that span nearly the full depth of the cartilage to the underlying subchondral bone. The lighter stained areas represent less severe cartilage degeneration. Note the smooth cartilage and lack of any staining on the lateral tibial plateau (right side), which is typical of this model. Figure 4B depicts the medial aspects of the tibial plateaus from 2 representative animals in the vehicle (saline) treated group. Again, deep focal lesions with an extended area of staining and fibrillation are present. Treatment with PB-145 reduced the depth and severity of lesions. Figure 4C shows medial tibial plateaus from the low-dose PB-145 group (100 ug/injection). Focal lesions are still present, but there are no full-thickness lesions, and the fibrillated area is shallower in depth, and staining with India ink is less intense. Figure 4D shows medial tibial plateaus from the high-dose PB-145 group (500 ug/injection). Instead of focal lesions, there is a thick layer of cartilage with a rough, slightly fibrillated surface and faint India ink staining.

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