Inhibition of hypertrophy and improving chondrocyte differentiation by MMP-13 inhibitor small molecule encapsulated in alginate-chondroitin sulfate-platelet lysate hydrogel

Abstract

Background Mesenchymal stem cells are a promising cell source for chondrogenic differentiation and have been widely used in several preclinical and clinical studies. However, they are prone to an unwanted differentiation process towards hypertrophy that limits their therapeutic efficacy. Matrix metallopeptidase 13 (MMP-13) is a well-known factor regulated during this undesirable event. MMP-13 is a collagen degrading enzyme, which is also highly expressed in the hypertrophic zone of the growth plate and in OA cartilage. Accordingly, we investigated the effect of MMP-13 inhibition on MSC hypertrophy. Methods In this study, 5-bromoindole-2-carboxylic acid (BICA) was used as an inhibitory agent for MMP-13 expression. After identifying its optimal concentration, BICA was mixed into a hydrogel and the release rate was studied. To prepare the ideal hydrogel, chondroitin sulfate (CS) and platelet lysate (PL) were mixed with sodium alginate (Alg) at concentrations selected based on synergistic mechanical and rheometric properties. Then, four hydrogels were prepared by combining alginate (1.5%w/v) and/or CS (1%w/v) and/or PL (20%v/v). The chondrogenic potential and progression to hypertrophy of human bone marrow-derived mesenchymal stem cell (hBM-MSC)-loaded hydrogels were investigated under free swelling and mechanical loading conditions, in the presence and absence of BICA. Results Viability of hBM-MSCs seeded in the four hydrogels was similar. qRT-PCR revealed that BICA could successfully inhibit MMP-13 expression, which led to an inhibition of Coll X and induction of Coll-II, in both free swelling and loading conditions. The GAG deposition was higher in the group combining BICA and mechanical stimulation. Conclusions It is concluded that BICA inhibition of MMP-13 reduces MSC hypertrophy during chondrogenesis. Graphical abstract

Macro, Micro, and Molecular. Changes of the Osteochondral Interface in Osteoarthritis Development

“…Although they showed good results in in vitro experiments, they have not been successful in clinical trials due to the heterologous effects and musculoskeletal syndrome ( Li et al, 2011 ; Winer et al, 2018 ). Recent studies have been focusing on the topical use of MMP-13 inhibitors in the lesions to enhance the efficacy and limit its adverse effects ( Jahangir et al, 2020 ). However, more clinical trials are needed to justify its therapeutic effects in humans.…”

Functionalized Hydrogels for Cartilage Repair: The Value of Secretome-Instructive Signaling

“…The hydrogel should also allow the formation of non-hypertrophic functional cartilage tissue. The use of mechanical stimuli or the addition of elements with the potential to reduce hypertrophy, such as chondroitin sulfate, platelet lysate, 5-bromoindole-2-carboxylic acid (BICA) are some of the options [ 112 , 113 ]. Besides these properties, hydrogels need to be efficiently integrated into the host tissue in order for them to function properly.…”

ADAMTS-12: Functions and Challenges for a Complex Metalloprotease

“…ADAMTS-12 plays an important role in the regulation of chondrogenesis and cartilage development. Levels of ADAMTS-12 have been detected strongly upregulated during chondrogenesis and also in proliferating and hypertrophic chondrocytes (Jin et al, 2007;Bai et al, 2009a;Bai et al, 2009b;Jahangir et al, 2020). ADAMTS-12 role in chondrogenesis is related to an important chondrogenic regulator, Parathyroid Hormone-Related Peptide (PTHrP) (Rajagopal et al, 2020).…”