Targeting anti‐chondrogenic factors for the stimulation of chondrogenesis: A new paradigm in cartilage repair

Abstract

Trauma and age-related cartilage disorders represent a major global cause of morbidity, resulting in chronic pain and disability in patients. A lack of effective therapies, together with a rapidly aging population, creates an impressive clinical and economic burden on healthcare systems. In this scenario, experimental therapies based on transplantation or in situ stimulation of skeletal Mesenchymal Stem/progenitor Cells (MSCs) have raised great interest for cartilage repair. Nevertheless, the challenge of guiding MSC differentiation and preventing cartilage hypertrophy and calcification still needs to be overcome. While research has mostly focused on the stimulation of cartilage anabolism using growth factors, several issues remain unresolved prompting the field to search for novel solutions. Recently, inhibition of anti-chondrogenic regulators has emerged as an intriguing opportunity. Anti-chondrogenic regulators include extracellular proteins as well as intracellular transcription factors and microRNAs that act as potent inhibitors of pro-chondrogenic signals. Suppression of these inhibitors can enhance MSC chondrogenesis and production of cartilage matrix. We here review the current knowledge concerning different types of anti-chondrogenic regulators. We aim to highlight novel therapeutic targets for cartilage repair and discuss suitable tools for suppressing their anti-chondrogenic functions. Further effort is needed to unveil the therapeutic perspectives of this approach and pave the way for effective treatment of cartilage injuries in patients. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res.

Comparative impact of platelet rich plasma and transforming growth factor-β on chondrogenic differentiation of human adipose derived stem cells

“…Although upregulation of miR-101, 140, and 145 promotes chondroprotective effects and inhibits inflammatory side effects, miR-199 and miR-146 exert anti-chondrogenic roles by targeting SMAD1 and SMAD2/3, respectively. 25 Therefore, at early chondrogenesis, PRP stimulates angiogenesis and ECM neogenesis via the upregulation of miR-146 while at late chondrogenesis, facilitates ADSCs differentiation to Fig. 3.…”

Non-viral Gene Therapy for Osteoarthritis

“…Therefore, viral and non-viral approaches may be used to enhance chondrogenic differentiation of MSCs by stimulating it with genes encoding growth factors or transcription factors required for chondrogenic response in MSCs (Leijten et al, 2014;Raisin et al, 2016). Moreover, gene therapies can enhance MSC immunomodulatory properties as well as stimulate anabolic chondrocyte responses in damaged cartilage or even inhibit anti-chondrogenic factors (Lolli et al, 2018).…”

Biological perspectives and current biofabrication strategies in osteochondral tissue engineering

“…interleukin-1β/-6 and tumour necrosis factor-α) have been implicated in the development of cartilage degradation in osteoarthritic joints and activation of the nuclear factor kappa B pathway; which can also contribute to the inhibition of chondrogenesis in human MSCs [195,197,198,[200][201][202][203]. Subsequently, understanding and modulating the inflammatory environment is key and has been investigated through a range of approaches including co-cultured adipose-derived MSCs [204], growth factors [165,195,196], platelet-rich plasma [205][206][207][208], control of macrophage phenotype [209][210][211], inhibition of anti-chondrogenic factors [212], and inflammation modulating biomaterials [213,214].…”