Recombinant fibroblast growth factor-18 (sprifermin) enhances microfracture-induced cartilage healing.
Abstract: Posttraumatic osteoarthritis is a disabling condition impacting the mostly young and active population. In the present study, we investigated the impact of intra-articular sprifermin, a recombinant truncated fibroblast growth factor 18, on the outcome of microfracture treatment, a widely used surgical technique to enhance cartilage healing at the site of injury. For this study, we created a cartilage defect and performed microfracture treatment in fetlock joints of 18 horses, treated joints with one of three doses of sprifermin (10, 30, or 100 μg) or with saline, hyaluronan, and evaluated animals functional and structural outcomes over 24 weeks. For primary outcome measures, we performed histological evaluations and gene expression analysis of aggrecan, collagen types I and II, and cartilage oligomeric matrix protein in three regions of interest. As secondary outcome measures, we examined animals' lameness, performed arthroscopic, radiographic, and computed tomography (CT) scan imaging and gross morphology assessment. We detected the highest treatment benefit following 100 μg sprifermin treatment. The overall histological assessment showed an improvement in the kissing region, and the expression of constitutive genes showed a concentration-dependent enhancement, especially in the peri-lesion area. We detected a significant improvement in lameness scores, arthroscopic evaluations, radiography, and CT scans following sprifermin treatment when results from three dose-treatment groups were combined. Our results demonstrated, for the first time, an enhancement on microfracture outcomes following sprifermin treatment suggesting a cartilage regenerative role and a potential benefit of sprifermin treatment in early cartilage injuries.
© 2021 Orthopaedic Research Society. Published by Wiley Periodicals LLC.
Publication Date: 2021-05-12 PubMed ID: 33934397PubMed Central: PMC8560655DOI: 10.1002/jor.25063Google Scholar: Lookup
The Equine Research Bank provides access to a large database of publicly available scientific literature. Inclusion in the Research Bank does not imply endorsement of study methods or findings by Mad Barn.
- Journal Article
- Research Support
- N.I.H.
- Extramural
- Research Support
- U.S. Gov't
- Non-P.H.S.
Summary
This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.
This research investigates the use of sprifermin, a growth factor, to improve microfracture treatment outcomes and promote cartilage healing in horses with post-traumatic osteoarthritis. The results show that sprifermin treatment can enhance healing and potentially benefit patients with early cartilage injuries.
Objective of the Research
- The primary goal of the study was to evaluate the impact of intra-articular sprifermin, a recombinant fibroblast growth factor 18, on microfracture treatment of cartilage defects caused by osteoarthritis in horses.
- Microfracture treatment is a common surgical intervention aiming at regenerating damaged cartilage tissue.
Research Methodology
- To test the effects of sprifermin, cartilage defects were created in the fetlock joints of 18 horses, followed by microfracture treatment. The horses were then either treated with differing doses of sprifermin (10, 30, or 100 μg) or with saline, hyaluronan, as controls.
- Over the 24 weeks following treatment, the animals’ functional and structural outcomes were evaluated including histological evaluations and gene expression analysis focusing on several compounds that are key indicators of cartilage health.
- As well as exploring these primary outcome measures, the study also examined lameness in the animals and made use of arthroscopic, radiographic, and CT scan imaging.
Research Findings
- Results demonstrated that the application of 100 μg sprifermin led to the highest treatment benefit.
- Increased improvement was observed in histological assessments and gene expression analysis, particularly in the area surrounding the lesion.
- Significant improvements were also seen in lameness scores and in the results of arthroscopic evaluations, radiographic, and CT scan imaging when the results from all sprifermin-treated groups were combined.
Conclusion and Implications of the Research
- The research findings showed that sprifermin enhances the outcome of microfracture treatments, suggesting a potential role in cartilage regeneration.
- The benefits of sprifermin treatment could extend to early cartilage injury cases, leading to improved healing and potentially preventing the progression of osteoarthritis in these patients.
Cite This Article
APA
Hendesi H, Stewart S, Gibison ML, Guehring H, Richardson DW, Dodge GR.
(2021).
Recombinant fibroblast growth factor-18 (sprifermin) enhances microfracture-induced cartilage healing.
J Orthop Res, 40(3), 553-564.
https://doi.org/10.1002/jor.25063 Publication
Researcher Affiliations
- Department of Orthopaedic Surgery, McKay Orthopaedic Research Laboratory, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
- Department of Clinical Studies, New Bolton Center, University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania, USA.
- Department of Clinical Studies, New Bolton Center, University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania, USA.
- Merck KGaA, Darmstadt, Germany.
- Department of Clinical Studies, New Bolton Center, University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania, USA.
- Department of Orthopaedic Surgery, McKay Orthopaedic Research Laboratory, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
- Translational Musculoskeletal Research Center, Corporal Michael J Crescenz VA Medical Center, Philadelphia, Pennsylvania, USA.
MeSH Terms
- Animals
- Cartilage, Articular / pathology
- Fibroblast Growth Factors / metabolism
- Fibroblast Growth Factors / pharmacology
- Fibroblast Growth Factors / therapeutic use
- Fractures, Stress / drug therapy
- Horses
- Lameness, Animal / drug therapy
- Lameness, Animal / metabolism
- Lameness, Animal / pathology
Grant Funding
- P30 AR069619 / NIAMS NIH HHS
- R01 AR071340 / NIAMS NIH HHS
- I01 RX001321 / RRD VA
- I01 RX001213 / RRD VA
References
This article includes 46 references
- Steadman JR, Briggs KK, Rodrigo JJ. Outcomes of microfracture for traumatic chondral defects of the knee: average 11-year follow-up. Arthroscopy 19(5):477–484.
- Steadman JR, Rodkey WG, Briggs KK. Microfracture: Its History and Experience of the Developing Surgeon. Cartilage 1(2):78–86.
- Breinan HA, Martin SD, Hsu HP, Spector M. Healing of canine articular cartilage defects treated with microfracture, a type-II collagen matrix, or cultured autologous chondrocytes. J Orthop Res 18(5):781–789.
- Mithoefer K, McAdams T, Williams RJ. Clinical efficacy of the microfracture technique for articular cartilage repair in the knee: an evidence-based systematic analysis. Am J Sports Med 37(10):2053–2063.
- Oussedik S, Tsitskaris K, Parker D. Treatment of articular cartilage lesions of the knee by microfracture or autologous chondrocyte implantation: a systematic review. Arthroscopy 31(4):732–744.
- Furukawa T, Eyre DR, Koide S, Glimcher MJ. Biochemical studies on repair cartilage resurfacing experimental defects in the rabbit knee. J Bone Joint Surg Am 62(1):79–89.
- Knutsen G, Engebretsen L, Ludvigsen TC. Autologous chondrocyte implantation compared with microfracture in the knee. A randomized trial. J Bone Joint Surg Am 86(3):455–464.
- Guney A, Akar M, Karaman I. Clinical outcomes of platelet rich plasma (PRP) as an adjunct to microfracture surgery in osteochondral lesions of the talus. Knee Surg Sports Traumatol Arthrosc 23(8):2384–2389.
- Kang SW, Bada LP, Kang CS. Articular cartilage regeneration with microfracture and hyaluronic acid. Biotechnol Lett 30(3):435–439.
- Kuo AC, Rodrigo JJ, Reddi AH. Microfracture and bone morphogenetic protein 7 (BMP-7) synergistically stimulate articular cartilage repair. Osteoarthritis Cartilage 14(11):1126–1135.
- Yang HS, La WG, Bhang SH. Hyaline cartilage regeneration by combined therapy of microfracture and long-term bone morphogenetic protein-2 delivery. Tissue Eng Part A 17(13–14):1809–1818.
- Solheim E, Hegna J, Inderhaug E. Results at 10–14 years after microfracture treatment of articular cartilage defects in the knee. Knee Surg Sports Traumatol Arthrosc 24(5):1587–1593.
- Correa D, Somoza RA, Lin P. Sequential exposure to fibroblast growth factors (FGF) 2, 9 and 18 enhances hMSC chondrogenic differentiation. Osteoarthritis Cartilage 23(3):443–453.
- Davidson D, Blanc A, Filion D. Fibroblast growth factor (FGF) 18 signals through FGF receptor 3 to promote chondrogenesis. J Biol Chem 280(21):20509–20515.
- Ellsworth JL, Berry J, Bukowski T. Fibroblast growth factor-18 is a trophic factor for mature chondrocytes and their progenitors. Osteoarthritis Cartilage 10(4):308–320.
- Liu Z, Lavine KJ, Hung IH, Ornitz DM. FGF18 is required for early chondrocyte proliferation, hypertrophy and vascular invasion of the growth plate. Dev Biol 302(1):80–91.
- Ohbayashi N, Shibayama M, Kurotaki Y. FGF18 is required for normal cell proliferation and differentiation during osteogenesis and chondrogenesis. Genes Dev 16(7):870–879.
- Ellman MB, Yan D, Ahmadinia K. Fibroblast growth factor control of cartilage homeostasis. J Cell Biochem 114(4):735–742.
- Krejci P, Krakow D, Mekikian PB, Wilcox WR. Fibroblast growth factors 1, 2, 17, and 19 are the predominant FGF ligands expressed in human fetal growth plate cartilage. Pediatr Res 61(3):267–272.
- Naski MC, Colvin JS, Coffin JD, Ornitz DM. Repression of hedgehog signaling and BMP4 expression in growth plate cartilage by fibroblast growth factor receptor 3. Development 125(24):4977–4988.
- Yang W, Cao Y, Zhang Z. Targeted delivery of FGF2 to subchondral bone enhanced the repair of articular cartilage defect. Acta Biomater 69:170–182.
- Barr L, Getgood A, Guehring H. The effect of recombinant human fibroblast growth factor-18 on articular cartilage following single impact load. J Orthop Res 32(7):923–927.
- Moore EE, Bendele AM, Thompson DL. Fibroblast growth factor-18 stimulates chondrogenesis and cartilage repair in a rat model of injury-induced osteoarthritis. Osteoarthritis Cartilage 13(7):623–631.
- Gigout A, Guehring H, Froemel D. Sprifermin (rhFGF18) enables proliferation of chondrocytes producing a hyaline cartilage matrix. Osteoarthritis Cartilage 25(11):1858–1867.
- Sennett ML, Meloni GR, Farran AJE. Sprifermin treatment enhances cartilage integration in an in vitro repair model. J Orthop Res 36(10):2648–2656.
- Lohmander LS, Hellot S, Dreher D. Intraarticular sprifermin (recombinant human fibroblast growth factor 18) in knee osteoarthritis: a randomized, double-blind, placebo-controlled trial. Arthritis Rheumatol 66(7):1820–1831.
- Hochberg MC, Guermazi A, Guehring H. Effect of Intra-Articular Sprifermin vs Placebo on Femorotibial Joint Cartilage Thickness in Patients With Osteoarthritis: The FORWARD Randomized Clinical Trial. JAMA 322(14):1360–1370.
- Dahlberg LE, Aydemir A, Muurahainen N. A first-in-human, double-blind, randomised, placebo-controlled, dose ascending study of intra-articular rhFGF18 (sprifermin) in patients with advanced knee osteoarthritis. Clin Exp Rheumatol 34(3):445–450.
- Power J, Hernandez P, Guehring H. Intra-articular injection of rhFGF-18 improves the healing in microfracture treated chondral defects in an ovine model. J Orthop Res 32(5):669–676.
- Howard D, Wardale J, Guehring H, Henson F. Delivering rhFGF-18 via a bilayer collagen membrane to enhance microfracture treatment of chondral defects in a large animal model. J Orthop Res 33(8):1120–1127.
- Chu CR, Szczodry M, Bruno S. Animal models for cartilage regeneration and repair. Tissue Eng Part B Rev 16(1):105–115.
- McIlwraith CW, Fortier LA, Frisbie DD, Nixon AJ. Equine Models of Articular Cartilage Repair. Cartilage 2(4):317–326.
- Mainil-Varlet P, Van Damme B, Nesic D. A new histology scoring system for the assessment of the quality of human cartilage repair: ICRS II. Am J Sports Med 38(5):880–890.
- American Association of Equine Practitioners (AAEP). Lameness Exams: Evaluating the Lame Horse. .
- Goebel L, Orth P, Muller A. Experimental scoring systems for macroscopic articular cartilage repair correlate with the MOCART score assessed by a high-field MRI at 9.4 T--comparative evaluation of five macroscopic scoring systems in a large animal cartilage defect model. Osteoarthritis Cartilage 20(9):1046–1055.
- van den Borne MP, Raijmakers NJ, Vanlauwe J. International Cartilage Repair Society (ICRS) and Oswestry macroscopic cartilage evaluation scores validated for use in Autologous Chondrocyte Implantation (ACI) and microfracture. Osteoarthritis Cartilage 15(12):1397–1402.
- Little CB, Smith MM, Cake MA. The OARSI histopathology initiative - recommendations for histological assessments of osteoarthritis in sheep and goats. Osteoarthritis Cartilage 18 Suppl 3:S80–92.
- Boyce MK, Trumble TN, Carlson CS. Non-terminal animal model of post-traumatic osteoarthritis induced by acute joint injury. Osteoarthritis Cartilage 21(5):746–755.
- Cohen MM, Vela ND, Levine JE, Barnoy EA. Validating a new computed tomography atlas for grading ankle osteoarthritis. J Foot Ankle Surg 54(2):207–213.
- Meloni GR, Farran A, Mohanraj B. Recombinant human FGF18 preserves depth-dependent mechanical inhomogeneity in articular cartilage. Eur Cell Mater 38:23–34.
- Reker D, Kjelgaard-Petersen CF, Siebuhr AS. Sprifermin (rhFGF18) modulates extracellular matrix turnover in cartilage explants ex vivo. J Transl Med 15(1):250.
- Reker D, Siebuhr AS, Thudium CS. Sprifermin (rhFGF18) versus vehicle induces a biphasic process of extracellular matrix remodeling in human knee OA articular cartilage ex vivo. Sci Rep 10(1):6011.
- Frisbie DD, Cross MW, McIlwraith CW. A comparative study of articular cartilage thickness in the stifle of animal species used in human pre-clinical studies compared to articular cartilage thickness in the human knee. Vet Comp Orthop Traumatol 19(3):142–146.
- Tang J, Su N, Zhou S. Fibroblast Growth Factor Receptor 3 Inhibits Osteoarthritis Progression in the Knee Joints of Adult Mice. Arthritis Rheumatol 68(10):2432–2443.
- Valverde-Franco G, Binette JS, Li W. Defects in articular cartilage metabolism and early arthritis in fibroblast growth factor receptor 3 deficient mice. Hum Mol Genet 15(11):1783–1792.
- Wilke MM, Nydam DV, Nixon AJ. Enhanced early chondrogenesis in articular defects following arthroscopic mesenchymal stem cell implantation in an equine model. J Orthop Res 25(7):913–925.
Use Nutrition Calculator
Check if your horse's diet meets their nutrition requirements with our easy-to-use tool Check your horse's diet with our easy-to-use tool
Talk to a Nutritionist
Discuss your horse's feeding plan with our experts over a free phone consultation Discuss your horse's diet over a phone consultation
Submit Diet Evaluation
Get a customized feeding plan for your horse formulated by our equine nutritionists Get a custom feeding plan formulated by our nutritionists