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.

Knockout of hyaluronan synthase 1, but not 3, impairs formation of the retrocalcaneal bursa

“…HAS1 expression complements HAS2 during early development (20). Moreover, HAS1-deficient mice exhibit aberrant dermal wound healing and excessive fibrotic remodeling of the joint capsule (21, 22), but the in-vivo functions of HAS1 and HAS3 during skeletal development and growth remain largely unknown. Indeed, recent evidence highlights the role of HAS isoforms in accessory functions other than HA synthesis (10), with cross-talk between the isoforms representing a relatively un-explored niche.…”

Pirfenidone attenuates synovial fibrosis and postpones the progression of osteoarthritis by anti-fibrotic and anti-inflammatory properties in vivo and in vitro

“…PFD decreases the deposition of hydroxyapatite by osteoblasts in a dose-dependent manner, which may inhibit osteophyte formation [ 35 ]. Furthermore, PFD can reduce subchondral bone loss and fibrosis following murine knee cartilage injury [ 36 ]. However, the influence of PFD on FLSs from OA and its efficacy in the treatment of OA remains incompletely characterized.…”

“…Furthermore, the mechanism by which PFD influences the function of chondrocyte remains unclear. Although the study established that PFD reduces subchondral bone loss and fibrosis in murine knee cartilage [ 36 ], whether PFD is able to promote cartilage repair and its production requires additional research. Finally, OA induced by the modified Hulth method is posttraumatic and different from the degenerative OA occurring in the elderly.…”

Anti-Osteoarthritic Effects of a Mixture of Dried Pomegranate Concentrate Powder, Eucommiae Cortex, and Achyranthis Radix 5:4:1 (g/g) in a Surgically Induced Osteoarthritic Rabbit Model

“…The anti-fibrotic and anti-inflammatory drug pirfenidone shows efficacy against kidney and lung fibrosis. Pirfenidone may encourage tissue repair and prevent progression of post-traumatic OA [71]. The fibrosis that occurs in OA due to chronic inflammation limits joint movement, where stiffness of the joints is a major symptom of OA.…”