The Beneficial Effect of an Intra-articular Injection of Losartan on Microfracture-Mediated Cartilage Repair Is Dose Dependent

Abstract

Background: A previous publication demonstrated that the oral intake of losartan promoted microfracture-mediated hyaline-like cartilage repair in osteochondral defects of a rabbit knee model. However, an intra-articular (IA) injection of losartan may have direct beneficial effects on cartilage repair and has not been studied. Purpose: To determine the dosage and beneficial effects of an IA injection of losartan on microfracture-mediated cartilage repair and normal cartilage homeostasis. Study Design: Controlled laboratory study. Methods: Rabbits were divided into 5 groups (n = 6 each): a microfracture group (MFX group) and 4 different losartan treatment groups that received varying doses of IA losartan (0.1, 1, 10, and 100 mg per knee). An osteochondral defect (5 mm) was created in the trochlear groove cartilage of 1 limb in each rabbit, and 5 microfracture perforations were made in the osteochondral defect. Both the injured and the contralateral knee joints were injected with IA losartan immediately after microfracture and at 2 and 4 weeks after surgery. Rabbits were sacrificed at 6 weeks after surgery for analysis including gross observation, micro–computed tomography, histology, and reverse transcription quantitative polymerase chain reaction. Results: Micro–computed tomography and gross observation demonstrated comparable subchondral bone healing and hyaline-like cartilage morphology in the 0.1-, 1-, and 10-mg losartan groups relative to the MFX group. Conversely, the 100-mg losartan group showed neither bony defect healing nor cartilage repair. Histology revealed higher O’Driscoll scores and hyaline-like cartilage regeneration in the 1-mg losartan group compared with the MFX group. In contrast, the 100-mg losartan group showed the lowest histology score and no cartilage repair. An IA injection of losartan at the doses of 0.1, 1, and 10 mg did not cause adverse effects on uninjured cartilage, while the 100-mg dose induced cartilage damage. Quantitative polymerase chain reaction results showed downregulation of the transforming growth factor β (TGF-β) signaling pathway after IA losartan injection. Conclusion: An IA injection of losartan at the dose of 1 mg was most effective for the enhancement of microfracture-mediated cartilage repair without adversely affecting uninjured cartilage. Conversely, a high dose (100 mg) IA injection of losartan inhibited cartilage repair in the osteochondral defect and was chondrotoxic to normal articular cartilage. Clinical Relevance: An IA injection of losartan at an optimal dosage represents a novel microfracture enhancement therapy and warrants a clinical trial for future clinical applications.

Pleiotropic Effects of Simvastatin and Losartan in Preclinical Models of Post-Traumatic Elbow Contracture

“…Contrary to the structural/ composition benefits (e.g., prevention of fibrillations and erosions) of drug treatment on cartilage seen in these previous preclinical studies, there was no robust tissue-level improvement with most SV and LS strategies in this study. However, recent work has shown LS at higher dosages can halt cartilage repair and induce cartilage damage in healthy cartilage (Logan et al, 2021), which somewhat aligns with the deleterious effects of LS strategies in this study. Collectively, these discrepancies could be due to the dosing strategy, joint location (e.g., anterior vs. posterior), joint studied (e.g., elbow vs. knee), type of arthritis (e.g., rheumatoid arthritis vs. post-trauma osteoarthritis), and type of traumatic insult (e.g., trauma, immobilization, chemical, or combinations).…”

“…For example, SV is thought to prevent cartilage damage by enhancing chondrogenesis (e.g., increased proteoglycan synthesis) and reducing chondrocyte production of harmful biochemical factors (e.g., inflammatory cytokines and matrix-degrading enzymes) ( Yudoh and Karasawa, 2010 ; Aktas et al, 2011 ). LS appears to provide similar cartilage structure protection in the knee ( Chen R. et al, 2015 ; Huard et al, 2018 ; Utsunomiya et al, 2020 ; Logan et al, 2021 ) but can also accelerate chondrocyte enlargement/hypertrophy in the growth plate ( Chen S. et al, 2015 ). Contrary to the structural/composition benefits (e.g., prevention of fibrillations and erosions) of drug treatment on cartilage seen in these previous preclinical studies, there was no robust tissue-level improvement with most SV and LS strategies in this study.…”

“…These properties have led to the primary clinical use of SV and LS to treat hypercholesterolemia and hypertension, respectively, although these drugs have recently been considered for treating arthritis due to their potential ability to suppress inflammation in the joint capsule and synovial fluid, resulting in reduced cartilage damage ( Cojocaru et al, 2013 ; Veronese et al, 2019 ; Wu et al, 2019 , 2020 ). Additional preclinical studies show benefits of administration of both drugs in other diseases, including cartilage damage and joint swelling in the knee ( Price et al, 2007 ; Yudoh and Karasawa, 2010 ; Aktas et al, 2011 ; Chen R. et al, 2015 ; Hamilton et al, 2018 ; Huard et al, 2018 ; Utsunomiya et al, 2020 ; Logan et al, 2021 ) and tissue fibrosis in the knee ( Baranowski et al, 2019 ), lungs ( Bagnato et al, 2013 ; Guo et al, 2015 ), muscle ( Bedair et al, 2008 ; Burks et al, 2011 ; Kobayashi et al, 2013 ; Davis et al, 2015 ; Whitehead et al, 2015 ; Huard et al, 2018 ), and heart ( Varo et al, 1999 ; Spurney et al, 2011 ; Sun et al, 2015 ; Böckmann et al, 2019 ; Kuo et al, 2019 ). Collectively, the aforementioned studies in the knee and other soft-tissues holistically suggest that both drugs might modulate fibroblasts/myofibroblasts and chondrocytes biology in the elbow joint post-trauma.…”

Capsulolabral Adhesions After Hip Arthroscopy for the Treatment of Femoroacetabular Impingement: Strategies During Rehabilitation and Return to Sport to Reduce the Risk of Revision

“… 27 and Logan et al. 28 found that when biologically regulated bone marrow stimulation was performed in conjunction to oral losartan intake, the cartilage repair was superior to the control population, resulting in increased hyaline cartilage formation and reduced fibrocartilage formation.…”

Sustained-release losartan from peptide nanofibers promotes chondrogenesis

“…However, there is concern about potential side effects of oral administration of the drug, which is an antihypertensive agent. While Logan et al showed that intra-articular injection of losartan promotes cartilage regeneration, they also reported that higher doses of losartan inhibit cartilage regeneration ( Logan et al, 2021 ), suggesting that there is a dose-dependent regenerative response of cartilage to losartan. Furthermore, as a low molecular weight (Mw) drug (Mw < 10,000 Da), losartan can easily diffuse through the interstitium and capillary walls ( Gerwin et al, 2006 ) and is expected to disappear from the joint in a few days.…”