title: IGFBP-5 Metabolism Is Disrupted in the Rat Medial Meniscal Tear Model of Osteoarthritis.
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.
authors.affiliation: Pfizer Global Research and Development, Chesterfield, Missouri.
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Yates
authors.affiliation: Pfizer Global Research and Development, Chesterfield, Missouri.
authors.forename: Steven L
authors.initials: SL
authors.lastname: Settle
authors.affiliation: Pfizer Global Research and Development, Chesterfield, Missouri.
authors.forename: Sue A
authors.initials: SA
authors.lastname: Yocum
authors.affiliation: Pfizer Global Research and Development, Chesterfield, Missouri.
authors.forename: Poonam
authors.initials: P
authors.lastname: Aggarwal
authors.affiliation: Pfizer Global Research and Development, Chesterfield, Missouri.
authors.forename: Lillian E
authors.initials: LE
authors.lastname: Vickery
authors.affiliation: Pfizer Global Research and Development, Chesterfield, Missouri.
authors.forename: Dean J
authors.initials: DJ
authors.lastname: Aguiar
authors.affiliation: Pfizer Global Research and Development, Chesterfield, Missouri.
authors.forename: Adam P
authors.initials: AP
authors.lastname: Skepner
authors.affiliation: Pfizer Global Research and Development, Chesterfield, Missouri.
authors.forename: Debra
authors.initials: D
authors.lastname: Kellner
authors.affiliation: Pfizer Global Research and Development, Chesterfield, Missouri.
authors.forename: Scott L
authors.initials: SL
authors.lastname: Weinrich
authors.affiliation: Pfizer Global Research and Development, Chesterfield, Missouri.
authors.forename: Francis M
authors.initials: FM
authors.lastname: Sverdrup
keywords: insulin-like growth factor 1; insulin-like growth factor binding protein 5