Abstract
ABSTRACTOne possible approach to treat osteoarthritis (OA) is to counteract cartilage degeneration with anabolic compounds that stimulate chondrocyte proliferation and/or extracellular matrix (ECM) production. Several molecules including sprifermin (recombinant human fibroblast growth factor [FGF18]), insulin‐like growth factor‐1 [IGF1] and ‐2 [IGF2], C‐type natriuretic peptide [CNP], and bone metamorphic protein 7 [BMP7] have been shown to have these characteristics both in vitro and in vivo. However, it is not known how these molecules compare each other regarding their effect on phenotype and stimulation of ECM production in primary chondrocytes. The effects of sprifermin, IGF1, IGF2, CNP, and BMP7 were evaluated on bovine articular chondrocytes, first in monolayer to determine their effective concentrations, and then in three‐dimensional (3D) culture at concentrations of 100 ng/ml for sprifermin; 300 ng/ml for IGF1, IGF2, and BMP7; and 10 nM for CNP. In 3D culture, the effects of a permanent exposure or a cyclic exposure consisting of 24 h incubation per week with the compounds were evaluated. All growth factors increased ECM production and cell proliferation to a similar extent but CNP had almost no effect on bovine chondrocytes. Sprifermin was more effective with cyclic exposure, IGF1, and IGF2 with permanent exposure, and BMP7 showed similar results with both exposures. Regarding the cell phenotype, sprifermin appeared to be the only compound favoring the chondrocyte phenotype; it decreased type I collagen expression and had no hypertrophic effect. Together, these results confirmed that sprifermin is a promising disease‐modifying OA drug. © 2019 The Authors. Journal of Orthopaedic Research ® published by Wiley Periodicals, Inc. on behalf of Orthopaedic Research Society. J Orthop Res 38:653–662, 2020
Highlights
Osteoarthritis (OA) is a degenerative joint disease affecting various tissues in the joint, with cartilage degradation being the hallmark of the disease
bone metamorphic protein 7 (BMP7) was obtained from R&D System (Minneapolis, MN), Insulin‐like growth factor 1 (IGF1) and IGF2 were from Merck‐Millipore (Darmstadt, Germany) and C‐type natriuretic peptide (CNP) from Sigma‐Aldrich
Effects of IGF1, IGF2, CNP, BMP7, and Sprifermin in Monolayer The cells were treated with 0.3–1,000 ng/ml of IGF1, IGF2, BMP7, or sprifermin and 0.003–10 μM of CNP for 7 days; and the cell number, GAG production, and gene expression were measured
Summary
Osteoarthritis (OA) is a degenerative joint disease affecting various tissues in the joint, with cartilage degradation being the hallmark of the disease. The two main target strategies for potential DMOADs are either anti‐catabolic (which aims to stop the process of cartilage degradation) or pro‐anabolic (which aims to stimulate the growth of new, healthy cartilage). IGF1 has been shown to stimulate cell proliferation and to increase proteoglycan and collagen production in vitro, and to promote cartilage repair in vivo.[6,7,8,9] The anabolic effect of IGF2 on chondrocytes or cartilage has been less extensively investigated but there are reports that. BMP7 has been shown to stimulate the production of proteoglycan[11] and the expression of aggrecan and type II collagen[12] in vitro, and to inhibit OA progression in vivo.[13] BMP7 entered clinical development[14,15] but no efficacy data have been reported
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