Current Applications of Growth Factors for Knee Cartilage Repair and Osteoarthritis Treatment

Abstract

Purpose of review: The decreased contact area, edge loading, and increased stress in the adjacent area cartilage resulting from chondral defects are believed to predispose this tissue to degenerative changes that have significant economic implications, especially when considering its progression to osteoarthritis of the knee. Growth factors are considered therapeutic possibilities to enhance healing of chondral injuries and modify the progression to degenerative arthritis. Thus, the purposes of this review are to first to summarize important points for defect preparation and recent advances in techniques for marrow stimulation and second, and to identify specific growth factors and cytokines that have the capacity to advance cartilage regeneration and the treatment of osteoarthritis in light of recent laboratory and clinical studies.

Recent findings: TGF-β, BMP-2, BMP-7, IGF-1, as IL-1 receptor antagonist, and recombinant human FGF-18 are some of the promising growth factor/cytokine treatments with pioneering and evolving clinical developments. The bulk of the review describes and discusses these developments in light of fundamental basic science. It is crucial to also understand the other underlying advances made in the surgical management of cartilage defects prior to onset of OA. These advances are in techniques for defect preparation and marrow stimulation, a common cartilage repair procedure used in combination with growth factor/cytokine augmentation. Multiple growth factor/cytokine modulation therapies are currently undergoing clinical trial investigation including Invossa (currently in phase III study), Kineret (currently in phase I study), and Sprifermin (currently in phase II study) for the treatment of symptomatic osteoarthritis.

Keywords: Cartilage repair; Cytokine; Growth factor; Osteoarthritis.

Fig. 1

Pictorial representation of biologic augmentation options for cartilage repair. After marrow stimulation, various biologic options influence (1) chondrogenic differentiation of mesenchymal stem cells (MSCs), (2) Sox-9 expression in MSCs, (3) cartilaginous extracellular matrix (ECM) production in MSCs, (4) chondrocyte proliferation, and (5) synthesis and retention of ECM within articular cartilage. Terms: bone morphogenetic protein 7 (BMP-7) and bone morphogenetic protein 2 (BMP-2)

Fig. 2

Structural effects of intra-articular Invossa (TissueGene-C (TissueGene Inc., Rockville, MD, USA)) in moderate to advanced knee osteoarthritis. Axial intermediate-weighted fat-suppressed MRI in treated patient at baseline (a) and 12 months (b) follow-up show improvement of cartilage focal defect and thickness of the medial patella (long arrows). Also note the decrease in volume of the joint effusion (small arrows). Guermazi, A., Kalsi, G., Niu, J. et al. Structural effects of intra-articular TGF-β1 in moderate to advanced knee osteoarthritis: MRI-based assessment in a randomized controlled trial. BMC Musculoskelet Disord 18, 461 (2017). 10.1186/s12891-017-1830-8. For articles published under an open access Creative Common CC BY license, any part of the article may be reused without permission provided that the original article is clearly cited

Fig. 3

Strategies for IL-1 blockade with Kineret (Anakinra (Swedish Orphan Biovitrum AB, Sweden)). a Interleukin (IL)-1 binds to type 1 IL-1 receptor (IL-1R1) and to the adaptor protein, IL-1RAcP, in order to trigger signal transduction. b The recombinant human IL-1R1 antagonist, Anakinra, directly competes with IL-1 for binding to the IL-1R1, blocking the biological activity of IL-1. Bettiol A, Lopalco G, Emmi G, et al. Unveiling the Efficacy, Safety, and Tolerability of Anti-Interleukin-1 Treatment in Monogenic and Multifactorial Autoinflammatory Diseases. Int J Mol Sci. 2019;20(8):1898. Published 2019 Apr 17. doi:10.3390/ijms20081898. For articles published under an open access Creative Common CC BY license, any part of the article may be reused without permission provided that the original article is clearly cited

Fig. 4

Sprifermin ((rhFGF18); (EMD Serono Inc., Rockland MA, subsidiary of Merck KGaA, Germany)] enables proliferation of chondrocytes producing a hyaline cartilage matrix. The histology results correspond well to the biochemical and gene expression results. In the 3D constructs cultured in the absence of sprifermin, no Safranin O or type II collagen staining was visible, but the constructs were positive for type I collagen, illustrating that these chondrocytes were not able to produce a cartilage-like extracellular matrix. In the presence of both permanent and 1 day/week sprifermin, a Safranin O and type II collagen-positive matrix was observed, while type I collagen staining was less intense in comparison to the control. Gigout A, Guehring H, Froemel D, et al. Sprifermin (rhFGF18) enables proliferation of chondrocytes producing a hyaline cartilage matrix. Osteoarthritis Cartilage. 2017;25(11):1858–1867. For articles published under an open access Creative Common CC BY license, any part of the article may be reused without permission provided that the original article is clearly cited