A promising novel formulation for articular cartilage regeneration: Preclinical evaluation of a treatment that produces SOX9 overexpression in human synovial fluid cells

Delgado‑Enciso,Ivan; Paz‑Garcia,Juan; Rodriguez‑Hernandez,Alejandrina; Madrigal‑Perez,Violeta M.; Cabrera‑Licona,Ariana; Garcia‑Rivera,Alejandro; Soriano‑Hernandez,Alejandro D.; Cortes‑Bazan,Jose L.; Galvan‑Salazar,Hector R.; Valtierra‑Alvarez,Jose; Guzman‑Esquivel,Jose; Rodriguez‑Sanchez,Iram P.; Martinez‑Fierro,Margarita L.; Paz‑Michel,Brenda

doi:10.3892/mmr.2017.8336

A promising novel formulation for articular cartilage regeneration: Preclinical evaluation of a treatment that produces SOX9 overexpression in human synovial fluid cells

Authors:
- Ivan Delgado‑Enciso
- Juan Paz‑Garcia
- Alejandrina Rodriguez‑Hernandez
- Violeta M. Madrigal‑Perez
- Ariana Cabrera‑Licona
- Alejandro Garcia‑Rivera
- Alejandro D. Soriano‑Hernandez
- Jose L. Cortes‑Bazan
- Hector R. Galvan‑Salazar
- Jose Valtierra‑Alvarez
- Jose Guzman‑Esquivel
- Iram P. Rodriguez‑Sanchez
- Margarita L. Martinez‑Fierro
- Brenda Paz‑Michel
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Affiliations: Cancerology State Institute, Colima State Health Services, Colima 28000, Mexico, Centro Hospitalario Union, Villa de Álvarez, Colima 28950, Mexico, School of Medicine, University of Colima, Colima 28030, Mexico, Esteripharma México, S.A. de C.V., Ciudad de México 03100, Mexico, Hospital Regional Universitario, Colima State Health Services, Colima 28000, Mexico, Hospital General de Zona No. 1 IMSS, Villa de Álvarez, Colima 28983, Mexico, Department of Genetics, School of Medicine, Nuevo Leon Autonomous University, Monterrey, Nuevo León 64460, Mexico, Molecular Medicine Laboratory, Academic Unit of Human Medicine and Health Sciences, Universidad Autónoma de Zacatecas, Zacatecas 98160, México
Published online on: December 20, 2017 https://doi.org/10.3892/mmr.2017.8336
Pages: 3503-3510
Copyright: © Delgado‑Enciso et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Osteoarthritis (OA) is a chronic disorder of synovial joints, in which there is progressive softening and disintegration of the articular cartilage. OA is the most common form of arthritis, and is the primary cause of disability and impaired quality of life in the elderly. Despite considerable medical necessity, no treatment has yet been proven to act as a disease‑modifying agent that may halt or reverse the structural progression of OA. The replacement of the joint with a prosthesis appears to be the best option in the advanced stages of the disease. A formulation (BIOF2) for cartilage regeneration has been recently developed. The present study evaluated the effects of BIOF2 on gene expression in human cell cultures, followed by efficacy trials in three OA animal models. Human synovial fluid cells that were exposed to the formulation exhibited increased transcription factor SOX‑9 (SOX9; chondrogenic factor) expression, and decreased mimecan (mineralization inducer) and macrophage‑stimulating protein receptor (osteoclastogenic factor) expression. The intra‑articular application of BIOF2 in the animal models significantly increased cartilage thickness from 12 to 31% at 28 days, compared with articular cartilage treated with saline solution. The articular area and number of chondrocytes additionally increased significantly, maintaining an unaltered chondrocyte/mm2 proportion. Evaluation of the histological architecture additionally displayed a decrease in the grade of articular damage in the groups treated with BIOF2. In conclusion, BIOF2 has proven to be effective for treating OA in animal models, most likely due to SOX9 overexpression in articular cells.

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1	Vaishya R, Pariyo GB, Agarwal AK and Vijay V: Non-operative management of osteoarthritis of the knee joint. J Clin Orthop Trauma. 7:170–176. 2016. View Article : Google Scholar : PubMed/NCBI
2	Karsdal MA, Michaelis M, Ladel C, Siebuhr AS, Bihlet AR, Andersen JR, Guehring H, Christiansen C, Bay-Jensen AC and Kraus VB: Disease-modifying treatments for osteoarthritis (DMOADs) of the knee and hip: Lessons learned from failures and opportunities for the future. Osteoarthritis Cartilage. 24:2013–2021. 2016. View Article : Google Scholar : PubMed/NCBI
3	Raeissadat SA, Rayegai SM, Hassanbadi H, Fathi M, Ghorbani E, Babaee M and Azma K: Knee osteoarthritis injection choices: Platelet-rich plasma (PRP) verses hyaluronic acid (A one year randomized clinical trial). Clin Med Insights Arthritis Musculoskelet Disord. 8:1–8. 2015. View Article : Google Scholar : PubMed/NCBI
4	Bannuru RR, Osani M, Vaysbrot EE and McAlindon TE: Comparative safety profile of hyaluronic acid products for knee osteoarthritis: A systematic reviewand network meta-analysis. Osteoarthritis Cartilage. 24:2022–2024. 2016. View Article : Google Scholar : PubMed/NCBI
5	Herrera-Espiñeira C, Escobar A, Navarro-Espigares JL, Castillo Jde D, García-Pérez L and Godoy-Montijano A: Total knee and hip prosthesis: Variables associated with costs. Cir Cir. 81:207–213. 2013.PubMed/NCBI
6	Hawker GA, Badley EM, Borkhoff CM, Croxford R, Davis AM, Dunn S, Gignac MA, Jaglal SB, Kreder HJ and Sale JE: Which patients are most likely to benefit from total joint arthroplasty? Arthritis Rheum. 65:1243–1252. 2013. View Article : Google Scholar : PubMed/NCBI
7	Montañez-Heredia E, Irízar S, Huertas PJ, Otero E, Del Valle M, Prat I, Díaz-Gallardo MS, Perán M, Marchal JA and Hernandez-Lamas Mdel C: Intra-Articular injections of Platelet-Rich plasma versus hyaluronic acid in the treatment of osteoarthritic knee pain: A randomized clinical trial in the context of the Spanish national health care system. Int J Mol Sci. 17(pii): E10642016. View Article : Google Scholar : PubMed/NCBI
8	Richter W: Cell-based cartilage repair: Illusion or solution for osteoarthritis. Curr Opin Rheumatol. 19:451–456. 2007.PubMed/NCBI
9	Uth K and Trifonov D: Stem cell application for osteoarthritis in the knee joint: A minireview. World J Stem Cells. 6:629–636. 2014. View Article : Google Scholar : PubMed/NCBI
10	Jakobsen RB, Østrup E, Zhang X, Mikkelsen TS and Brinchmann JE: Analysis of the effects of five factors relevant to in vitro chondrogenesis of human mesenchymal stem cells using factorial design and high throughput mRNA-profiling. PLoS One. 9:e966152014. View Article : Google Scholar : PubMed/NCBI
11	Tangtrongsup S and Kisiday JD: Effects of dexamethasone concentration and timing of exposure on chondrogenesis of equine bone Marrow-derived mesenchymal stem cells. Cartilage. 7:92–103. 2016. View Article : Google Scholar : PubMed/NCBI
12	Scioli MG, Bielli A, Gentile P, Cervelli V and Orlandi A: Combined treatment with platelet-rich plasma and insulin favours chondrogenic and osteogenic differentiation of human adipose-derived stem cells in three-dimensional collagen scaffolds. J Tissue Eng Regen Med. 11:2398–2410. 2017. View Article : Google Scholar : PubMed/NCBI
13	Yao Y, Zhai Z and Wang Y: Evaluation of insulin medium or chondrogenic medium on proliferation and chondrogenesis of ATDC5 cells. Biomed Res Int. 2014:5692412014. View Article : Google Scholar : PubMed/NCBI
14	Gerstenfeld LC, Toma CD, Schaffer JL and Landis WJ: Chondrogenic potential of skeletal cell populations: Selective growth of chondrocytes and their morphogenesis and development in vitro. Microsc Res Tech. 43:156–173. 1998. View Article : Google Scholar : PubMed/NCBI
15	Paz-García J and Paz-Michel BA: Formulation for regeneration of bone, cartilage, teeth, and periodontium and treatment of tumors and cysts US Patent US9089580 B1. July 28–2015, issued February 4, 2015.
16	Casnici C, Lattuada D, Tonna N, Crotta K, Storini C, Bianco F, Truzzi MC, Corradini C and Marelli O: Optimized ‘in vitro’ culture conditions for human rheumatoid arthritis synovial fibroblasts. Mediators Inflamm. 2014:7020572014. View Article : Google Scholar : PubMed/NCBI
17	Li XW, Tuergan M and Abulizi G: Expression of MAPK1 in cervical cancer and effect of MAPK1 gene silencing on epithelial-mesenchymal transition, invasion and metastasis. Asian Pac J Trop Med. 8:937–943. 2015. View Article : Google Scholar : PubMed/NCBI
18	Mayer S, Hirschfeld M, Jaeger M, Pies S, Iborra S, Erbes T and Stickeler E: RON alternative splicing regulation in primary ovarian cancer. Oncol Rep. 34:423–430. 2015. View Article : Google Scholar : PubMed/NCBI
19	Biason-Lauber A, Konrad D, Meyer M, DeBeaufort C and Schoenle EJ: Ovaries and female phenotype in a girl with 46,XY karyotype and mutations in the CBX2 gene. Am J Hum Genet. 84:658–663. 2009. View Article : Google Scholar : PubMed/NCBI
20	O'Neill CF, Urs S, Cinelli C, Lincoln A, Nadeau RJ, León R, Toher J, Mouta-Bellum C, Friesel RE and Liaw L: Notch2 signaling induces apoptosis and inhibits human MDA-MB-231 xenograft growth. Am J Pathol. 171:1023–1036. 2007. View Article : Google Scholar : PubMed/NCBI
21	Shin JE, Oh JH, Kim YK, Jung JY and Chung JH: Transcriptional regulation of proteoglycans and glycosaminoglycan chain-synthesizing glycosyltransferases by UV irradiation in cultured human dermal fibroblasts. J Korean Med Sci. 26:417–424. 2011. View Article : Google Scholar : PubMed/NCBI
22	Pottosin I, Delgado-Enciso I, Bonales-Alatorre E, Nieto-Pescador MG, Moreno-Galindo EG and Dobrovinskaya O: Mechanosensitive Ca²⁺-permeable channels in human leukemic cells: Pharmacological and molecular evidence for TRPV2. Biochim Biophys Acta. 1848:51–59. 2015. View Article : Google Scholar : PubMed/NCBI
23	Ma HL, Blanchet TJ, Peluso D, Hopkins B, Morris EA and Glasson SS: Osteoarthritis severity is sex dependent in a surgical mouse model. Osteoarthritis Cartilage. 15:695–700. 2007. View Article : Google Scholar : PubMed/NCBI
24	van der Kraan PM, Vitters EL, van de Putte LB and van den Berg WB: Development of osteoarthritic lesions in mice by ‘metabolic’ and ‘mechanical’ alterations in the knee joints. Am J Pathol. 135:1001–1014. 1989.PubMed/NCBI
25	Stoop R, van der Kraan PM, Buma P, Hollander AP, Billinghurst RC, Poole AR and van den Berg WB: Type II collagen degradation in spontaneous osteoarthritis in C57Bl/6 and BALB/c mice. Arthritis Rheum. 42:2381–2389. 1999. View Article : Google Scholar : PubMed/NCBI
26	Moriizumi T, Yamashita N and Okada Y: Papain-induced changes in the guinea pig knee joint with special reference to cartilage healing. Virchows Arch B Cell Pathol Incl Mol Pathol. 51:461–474. 1986. View Article : Google Scholar : PubMed/NCBI
27	Hardin JA, Cobelli N and Santambrogio L: Consequences of metabolic and oxidative modifications of cartilage tissue. Nat Rev Rheumatol. 11:521–529. 2015. View Article : Google Scholar : PubMed/NCBI
28	Fazelipour S, Tootian Z, Matini E and Hadipour-Jahromy M: Histomorphometric alteration of knee articular cartilage and serum alkaline phosphatase in young female mice by chronic supplementation with soybean. Phytother Res. 25:886–891. 2011. View Article : Google Scholar : PubMed/NCBI
29	Chambers MG, Cox L, Chong L, Suri N, Cover P, Bayliss MT and Mason RM: Matrix metalloproteinases and aggrecanases cleave aggrecan in different zones of normal cartilage but colocalize in the development of osteoarthritic lesions in STR/ort mice. Arthritis Rheum. 44:1455–1465. 2001. View Article : Google Scholar : PubMed/NCBI
30	Musumeci G, Loreto C, Castorina S, Imbesi R, Leonardi R and Castrogiovanni P: Current concepts in the treatment of cartilage damage. A review. Ital J Anat Embryol. 118:189–203. 2013.PubMed/NCBI
31	Bi W, Deng JM, Zhang Z, Behringer RR and de Crombrugghe B: Sox9 is required for cartilage formation. Nat Genet. 22:85–89. 1999. View Article : Google Scholar : PubMed/NCBI
32	Goldberg VM, Buckwalter J, Halpin M, Jiranek W, Mihalko W, Pinzur M, Rohan B, Vail T, Walker P, Windsor R and Wright T: Recommendations of the OARSI FDA Osteoarthritis Devices Working Group. Osteoarthritis Cartilage. 19:509–514. 2011. View Article : Google Scholar : PubMed/NCBI
33	Liao J, Hu N, Zhou N, Lin L, Zhao C, Yi S, Fan T, Bao W, Liang X, Chen H, et al: Sox9 potentiates BMP2-induced chondrogenic differentiation and inhibits BMP2-induced osteogenic differentiation. PLoS One. 9:e890252014. View Article : Google Scholar : PubMed/NCBI
34	Tao K, Frisch J, Rey-Rico A, Venkatesan JK, Schmitt G, Madry H, Lin J and Cucchiarini M: Co-overexpression of TGF-β and SOX9 via rAAV gene transfer modulates the metabolic and chondrogenic activities of human bone marrow-derived mesenchymal stem cells. Stem Cell Res Ther. 7:202016. View Article : Google Scholar : PubMed/NCBI
35	Wan R, Hu J, Zhou Q, Wang J, Liu P and Wei Y: Application of co-expressed genes to articular cartilage: New hope for the treatment of osteoarthritis (Review). Mol Med Rep. 6:16–18. 2012.PubMed/NCBI
36	Balakrishnan L, Nirujogi RS, Ahmad S, Bhattacharjee M, Manda SS, Renuse S, Kelkar DS, Subbannayya Y, Raju R, Goel R, et al: Proteomic analysis of human osteoarthritis synovial fluid. Clin Proteomics. 11:62014. View Article : Google Scholar : PubMed/NCBI
37	De Ceuninck F, Marcheteau E, Berger S, Caliez A, Dumont V, Raes M, Anract P, Leclerc G, Boutin JA and Ferry G: Assessment of some tools for the characterization of the human osteoarthritic cartilage proteome. J Biomol Tech. 16:256–265. 2005.PubMed/NCBI
38	Akiyama M, Nakahama K and Morita I: Impact of docosahexaenoic acid on gene expression during osteoclastogenesis in vitro-a comprehensive analysis. Nutrients. 5:3151–3162. 2013. View Article : Google Scholar : PubMed/NCBI
39	Cully M: Bone diseases: MST1R inhibitor prevents bone osteolysis. Nat Rev Drug Discov. 16:164–165. 2017. View Article : Google Scholar : PubMed/NCBI
40	Watanabe M, Tezuka Y, Matsuno K, Miyatani S, Morimura N, Yasuda M, Fujimaki R, Kuroda K, Hiraki Y, Hozumi N and Tezuka K: Suppresion of differentiation and proliferation of each chondrogenic cells by Notch. J Bone Miner Metab. 21:344–352. 2003. View Article : Google Scholar : PubMed/NCBI
41	Hardingham TE, Oldershaw RA and Tew SR: Cartilage, SOX9 and Notch signal in chondrogenesis. J Anat. 209:469–480. 2006. View Article : Google Scholar : PubMed/NCBI
42	Pei M, He F and Vunjak-Novakovic G: Synovium-derived stem cell-based chondrogenesis. Differentiation. 76:1044–1056. 2008. View Article : Google Scholar : PubMed/NCBI
43	Katagiri K, Matsukura Y, Muneta T, Ozeki N, Mizuno M, Katano H and Sekiya I: Fibrous synovium releases higher numbers of mesenchymal stem cells than adipose synovium in a suspended synovium culture model. Arthroscopy. 33:800–810. 2017. View Article : Google Scholar : PubMed/NCBI
44	Richards MM, Maxwell JS, Weng L, Angelos MG and Golzarian J: Intra-articular treatment of knee osteoarthritis: From anti-inflammatories to products of regenerative medicine. Phys Sportsmed. 44:101–108. 2016. View Article : Google Scholar : PubMed/NCBI
45	Rodriguez-Maerchan EC: Intra articular injection of hyaluronic acid and other drugs in knee joint. HSS J. 9:180–182. 2013. View Article : Google Scholar : PubMed/NCBI