Biologically Regulated Marrow Stimulation by Blocking TGF-β1 With Losartan Oral Administration Results in Hyaline-like Cartilage Repair: A Rabbit Osteochondral Defect Model

Abstract

Background: Microfracture or bone marrow stimulation (BMS) is often the first choice for clinical treatment of cartilage injuries; however, fibrocartilage, not pure hyaline cartilage, has been reported because of the development of fibrosis in the repair tissue. Transforming growth factor β1 (TGF-β1), which can promote fibrosis, can be inhibited by losartan and potentially be used to reduce fibrocartilage. Hypothesis: Blocking TGF-β1 would improve cartilage healing in a rabbit knee BMS model via decreasing the amount of fibrocartilage and increasing hyaline-like cartilage formation. Study Design: Controlled laboratory study. Methods: An osteochondral defect was made in the patellar groove of 48 New Zealand White rabbits. The rabbits were divided into 3 groups: a defect group (defect only), a BMS group (osteochondral defect + BMS), and a BMS + losartan group (osteochondral defect + BMS + losartan). For the rabbits in the BMS + losartan group, losartan was administrated orally from the day after surgery through the day of euthanasia. Rabbits were sacrificed 6 or 12 weeks postoperatively. Macroscopic appearance, microcomputed tomography, histological assessment, and TGF-β1 signaling pathway were evaluated at 6 and 12 weeks postoperatively. Results: The macroscopic assessment of the repair revealed that the BMS + losartan group was superior to the other groups tested. Microcomputed tomography showed superior healing of the bony defect in the BMS + losartan group in comparison with the other groups. Histologically, fibrosis in the repair tissue of the BMS + losartan group was significantly reduced when compared with the other groups. Results obtained with the modified O’Driscoll International Cartilage Repair Society grading system yielded significantly superior scores in the BMS + losartan group as compared with both the defect group and the BMS group ( F value: 15.8, P < .001, P = .012, respectively). TGF-β1 signaling and TGF-β-activated kinase 1 of the BMS + losartan group were significantly suppressed in the synovial tissues. Conclusion: By blocking TGF-β1 with losartan, the repair cartilage tissue after BMS was superior to the other groups and consisted primarily of hyaline cartilage. These results should be easily translated to the clinic because losartan is a Food and Drug Administration–approved drug and it can be combined with the BMS technique for optimal repair of chondral defects. Clinical Relevance: Biologically regulated marrow stimulation by blocking TGF-β1 (oral intake of losartan) provides superior repair via decreasing fibrocartilage formation and resulting in hyaline-like cartilage as compared with outcomes from BMS only.

Effect of Oral Losartan on Orthobiologics: Implications for Platelet-Rich Plasma and Bone Marrow Concentrate—A Rabbit Study

“…All animals were housed at the Center for Laboratory Animal Medicine and Care at the University of Texas Health Science Center at Houston and maintained according to approved Institutional Animal Care and Use Committee protocol (project identification code: AWC-17-0022, date of approval: 04/05/2017). The present study is an arm of a different study recently published that observed the effect of TGF-β1 blocking with losartan oral administration on rabbit cartilage repair after the creation of an osteochondral defect [ 45 ]. An osteochondral defect (5 mm in diameter and 2mm in depth) was made in the patellar groove of 10 New Zealand white rabbits that were divided into 2 groups (N = 5/group) randomly: a control group (osteochondral defect + microfracture, group 1) and losartan treated group (osteochondral defect + microfracture + losartan, group 2).…”

“…An osteochondral defect (5 mm in diameter and 2mm in depth) was made in the patellar groove of 10 New Zealand white rabbits that were divided into 2 groups (N = 5/group) randomly: a control group (osteochondral defect + microfracture, group 1) and losartan treated group (osteochondral defect + microfracture + losartan, group 2). More details of the surgical procedure are described in the main study [ 45 ]. A dose of 10mg/kg/day of losartan (Cozzar ® , Merck, Readington, NJ, USA), the equivalent treatment dose in a mouse muscle injury model [ 12 ], was administrated orally to the rabbits in group 2 starting post-op day one through the day of euthanasia (12 weeks).…”

Biphasic Double-Network Hydrogel With Compartmentalized Loading of Bioactive Glass for Osteochondral Defect Repair

“…TGF-β1 could play a positive role via promoting the proliferation and differentiation of mesenchymal stem cells (MSCs) as well as the synthesis and secretion of the specific cell matrix ( Zhen et al, 2013 ; Reyes et al, 2014 ; Zhou et al, 2017 ; Utsunomiya et al, 2020 ), but it could also exert an inhibiting effect. Some reports revealed that the concentration of TGF-β1 might play an imperative role, and local excessive concentration had the potential to inhibit the formation of new bone and cartilage, even resulting in osteoarthritis ( Zhen et al, 2013 ; Utsunomiya et al, 2020 ). Further studies are required to profoundly understand this controversial issue that how to maximize the performance of TGF-β1 for osteochondral defect repair.…”

Intra-articular Injection of Bevacizumab Enhances Bone Marrow Stimulation–Mediated Cartilage Repair in a Rabbit Osteochondral Defect Model

“…After the rabbits were anesthetized, an osteochondral defect (diameter, 5 mm; depth, 2 mm) was made in the patellar groove of the rabbits using a 5-mm dental drill trephine as described previously. 40 An osteochondral defect rather than a chondral defect was created, as previous animal studies have shown that there is a potential for healing without treatment when only the cartilage is damaged in rabbits. 33,46 Then, 5 holes were drilled immediately after the osteochondral defect using a 0.7-mm drill bur with 0.9-mm distance between holes and at a 2-mm depth.…”