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Pirfenidone reduces subchondral bone loss and fibrosis after murine knee cartilage injury.

ABSTRACT: Pirfenidone is an anti-inflammatory and anti-fibrotic drug that has shown efficacy in lung and kidney fibrosis. Because inflammation and fibrosis have been linked to the progression of osteoarthritis, we investigated the effects of oral Pirfenidone in a mouse model of cartilage injury, which results in chronic inflammation and joint-wide fibrosis in mice that lack hyaluronan synthase 1 (Has1-/- ) in comparison to wild-type. Femoral cartilage was surgically injured in wild-type and Has1-/- mice, and Pirfenidone was administered in food starting after 3 days. At 4 weeks, Pirfenidone reduced the appearance, on micro-computed tomography, of pitting in subchondral bone at, and cortical bone surrounding, the site of cartilage injury. This corresponded with a reduction in fibrotic tissue deposits as observed with gross joint surface photography. Pirfenidone resulted in significant recovery of trabecular bone parameters affected by joint injury in Has1-/- mice, although the effect in wild-type was less pronounced. Pirfenidone also increased Safranin-O staining of growth plate cartilage after cartilage injury and sham operation in both genotypes. Taken together with the expression of selected extracellular matrix, inflammation, and fibrosis genes, these results indicate that Pirfenidone may confer chondrogenic and bone-protective effects, although the well-known anti-fibrotic effects of Pirfenidone may occur earlier in the wound-healing response than the time point examined in this study. Further investigations to identify the specific cell populations in the joint and signaling pathways that are responsive to Pirfenidone are warranted, as Pirfenidone and other anti-fibrotic drugs may encourage tissue repair and prevent progression of post-traumatic osteoarthritis. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:365-376, 2018.

SUBMITTER: Chan DD

PROVIDER: S-EPMC5742076 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Pirfenidone reduces subchondral bone loss and fibrosis after murine knee cartilage injury.

Chan Deva D DD Li Jun J Luo Wei W Predescu Dan N DN Cole Brian J BJ Plaas Anna A

Journal of orthopaedic research : official publication of the Orthopaedic Research Society 20170721 1

Pirfenidone is an anti-inflammatory and anti-fibrotic drug that has shown efficacy in lung and kidney fibrosis. Because inflammation and fibrosis have been linked to the progression of osteoarthritis, we investigated the effects of oral Pirfenidone in a mouse model of cartilage injury, which results in chronic inflammation and joint-wide fibrosis in mice that lack hyaluronan synthase 1 (Has1<sup>-/-</sup> ) in comparison to wild-type. Femoral cartilage was surgically injured in wild-type and Has ...[more]

PMID: 28646530

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Project description:PurposeRecent studies demonstrated a contribution of adrenoceptors (ARs) to osteoarthritis (OA) pathogenesis. Several AR subtypes are expressed in joint tissues and the β2-AR subtype seems to play a major role during OA progression. However, the importance of β2-AR has not yet been investigated in knee OA. Therefore, we examined the development of knee OA in β2-AR-deficient (Adrb2-/- ) mice after surgical OA induction.MethodsOA was induced by destabilization of the medial meniscus (DMM) in male wildtype (WT) and Adrb2-/- mice. Cartilage degeneration and synovial inflammation were evaluated by histological scoring. Subchondral bone remodeling was analyzed using micro-CT. Osteoblast (alkaline phosphatase - ALP) and osteoclast (cathepsin K - CatK) activity were analyzed by immunostainings. To evaluate β2-AR deficiency-associated effects, body weight, sympathetic tone (splenic norepinephrine (NE) via HPLC) and serum leptin levels (ELISA) were determined. Expression of the second major AR, the α2-AR, was analyzed in joint tissues by immunostaining.ResultsWT and Adrb2-/- DMM mice developed comparable changes in cartilage degeneration and synovial inflammation. Adrb2-/- DMM mice displayed elevated calcified cartilage and subchondral bone plate thickness as well as increased epiphyseal BV/TV compared to WTs, while there were no significant differences in Sham animals. In the subchondral bone of Adrb2-/- mice, osteoblasts activity increased and osteoclast activity deceased. Adrb2-/- mice had significantly higher body weight and fat mass compared to WT mice. Serum leptin levels increased in Adrb2-/- DMM compared to WT DMM without any difference between the respective Shams. There was no difference in the development of meniscal ossicles and osteophytes or in the subarticular trabecular microstructure between Adrb2-/- and WT DMM as well as Adrb2-/- and WT Sham mice. Number of α2-AR-positive cells was lower in Adrb2-/- than in WT mice in all analyzed tissues and decreased in both Adrb2-/- and WT over time.ConclusionWe propose that the increased bone mass in Adrb2-/- DMM mice was not only due to β2-AR deficiency but to a synergistic effect of OA and elevated leptin concentrations. Taken together, β2-AR plays a major role in OA-related subchondral bone remodeling and is thus an attractive target for the exploration of novel therapeutic avenues.

Project description:AimsTo investigate the impact of subchondral bone cysts (SBCs) in stress-induced osseous and articular variations in cystic and non-cystic knee models using finite element analysis.Materials and methods3D knee joint models were reconstructed from computed tomography (CT) and magnetic resonance imaging (MRI). Duplicate 3D models were also created with a 3D sphere mimicking SBCs in medial tibia. Models were divided into three groups. In group A, a non-cystic knee model was used, whereas in groups B and C, SBCs of 4 and 12 mm size were simulated, respectively. Cyst groups were further divided into three sub-groups. Each of sub-group 1 was composed of a solitary SBC in the anterior half of tibia adjacent to joint line. In sub-group 2, a solitary cyst was modeled at a lower-joint location, and in sub-group 3, two SBCs were used. All models were vertically loaded with weights representing double- and single-leg stances.ResultsDuring single-leg stance, increase in subchondral bone stress in sub-groups B-1 and B-3 were significant (p = 0.044, p = 0.026). However, in sub-group B-2, a slight increase was observed than non-cystic knee model (9.93 ± 1.94 vs. 9.35 ± 1.85; p = 0.254). All the sub-groups in group C showed significantly increased articular stress (p < 0.001). Conversely, a prominent increase in peri-cystic cancellous bone stress was produced by SBCs in groups B and C (p < 0.001). Mean cartilage shear stress in sub-groups B-1 and B-2 (0.66 ± 0.56, 0.58 ± 0.54) was non-significant (p = 0.374, p = 0.590) as compared to non-cystic model (0.47 ± 0.67). But paired cysts of the same size (B-3) produced a mean stress of 0.98 ± 0.49 in affected cartilage (p = 0.011). Models containing 12 mm SBCs experienced a significant increase in cartilage stress (p = 0.001, p = 0.006, p < 0.001) in sub-groups C-1, C-2, and C-3 (1.25 ± 0.69, 1.01 ± 0.54, and 1.26 ± 0.59), respectively.ConclusionThe presence of large-sized SBCs produced an increased focal stress effect in articular cartilage. Multiple cysts further deteriorate the condition by increased osseous stress effect and high tendency of peripheral cyst expansion in simulated cystic knee models than non-cystic knee models.

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Pirfenidone reduces subchondral bone loss and fibrosis after murine knee cartilage injury.

Publications

Pirfenidone reduces subchondral bone loss and fibrosis after murine knee cartilage injury.

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