Regenerative approaches for cartilage repair in the treatment of osteoarthritis  M.H. Li, R. Xiao, J.B. Li, Q. Zhu  Osteoarthritis and Cartilage  Volume 25, Issue 10, Pages 1577-1587 (October 2017) DOI: 10.1016/j.joca.2017.07.004 Copyright © 2017 Osteoarthritis Research Society International Terms and Conditions

Fig. 1 Convergent pathogenic pathways of cartilage degradation in osteoarthritis and strategies in cartilage regenerative treatment. Chondrocytes, fibroblast-like synoviocytes (FLSs) and subchondral bone osteoblasts (SBOs) are shown. Mechanical stress and biochemical stimuli on chondrocytes result in increased production of proinflammatory mediators, extracellular matrix (ECM) degrading enzymes, and hypocellularity caused by apoptosis. Activation of NF-κB induces HIF-2α in chondrocytes, which leads to upregulated production of MMP-13 and MMP-3 to degrade ECM and induces expression of RUNX2, Ihh, Col10 and VEGF (not shown) to promote endochondral ossification. Increased expression of TGF-β is seen in SBO and FLS of OA and contributes to development of osteoarthritis. TGF-β signaling skewing from classical Smad2/3 to Smad1/5/8 leads to hypertrophic differentiation of chondrocytes. Inhibition of the inflammatory mediators or interruption of intracellular signaling pathways by mAbs, chemical compounds, and fusion proteins represents recent approaches to the strategies for anti-inflammatory and anti-degradative treatments. Cell-based or cell-homing therapies are a viable means for pro-chondrogenesis facilitating cartilage regeneration, including scaffolding systems containing stem cell homing factors (1, 2) or progenitor cell chemotaxis followed by chondrogenic stimulation (3), autologous or matrix-assisted autologous chondrocyte implantation (ACI or MACI) (4), in vivo generated cartilage from endogenous chondrogenic-differentiated stem cells (5), mesenchymal stem cell implantation (6), and growth factor-induced stem cell expansion and pro-chondrogenic differentiation with augmented ECM production (7). Integrated approach is a combined therapy that utilizes all means of most advanced technologies available targeted, genetic, and cellular therapies to treat and regenerate cartilage faster, safer and more accurately and effectively (8). Osteoarthritis and Cartilage 2017 25, 1577-1587DOI: (10.1016/j.joca.2017.07.004) Copyright © 2017 Osteoarthritis Research Society International Terms and Conditions

Fig. 2 Current and emerging principles of regenerative therapies for OA treatment. Current clinical approaches in regenerative treatment of OA concentrate mainly on the disease at moderate and advanced stages primarily using autologous mesenchymal stem cells (MSCs) and a variety of bioscaffolds, separately or in combination. Patients can alleviate their symptoms with various degrees of improved clinical outcomes. Specific homing of tissue-derived stem/progenitor cells to the site of cartilage defect using chemotactic agents or activation of resident cells with regenerative potential chemically or biologically is a nearly noninvasive approach, potentially more acceptable for patients having early sign of disease. MSC may be genetically modified or optimized for improvement in regenerative and reparative capabilities. Scaffolds and microfracture techniques are invasive treatments for later stages of OA. As the prevalence of OA is increasing and continues to rise markedly with age, earlier and less invasive therapeutic regimens may not only offer the possibility of halting disease progression more effectively but also increase the likelihood of cure for OA at earlier stages. Osteoarthritis and Cartilage 2017 25, 1577-1587DOI: (10.1016/j.joca.2017.07.004) Copyright © 2017 Osteoarthritis Research Society International Terms and Conditions