Triamcinolone acetonide activates an anti-inflammatory and folate receptor–positive macrophage that prevents osteophytosis in vivo

Abstract

IntroductionTriamcinolone acetonide (TA) is used for osteoarthritis management to reduce pain, and pre-clinical studies have shown that TA limits osteophyte formation. Osteophyte formation is known to be facilitated by synovial macrophage activation. TA injections might influence macrophage activation and subsequently reduce osteophytosis. Although widely applied in clinical care, the mechanism through which TA exerts this effect remains unknown. In this animal study, we investigated the in vivo effects of TA injections on macrophage activation, osteophyte development and joint degeneration. Furthermore, in vitro macrophage differentiation experiments were conducted to further explain working mechanisms of TA effects found in vivo.MethodsOsteoarthritis was induced in rat knees using papain injections and a running protocol. Untreated and TA-treated animals were longitudinally monitored for 12 weeks with in vivo micro–computed tomography (μCT) to measure subchondral bone changes. Synovial macrophage activation was measured in vivo using folate receptor β (FRβ)-targeted single-photon emission computed tomography/computed tomography. Articular cartilage was analyzed at 6 and 12 weeks with ex vivo contrast-enhanced μCT and histology. To further explain the outcomes of our in vivo study, TA on macrophages was also studied in vitro. These cultured macrophages were either M1- or M2-activated, and they were analyzed using fluorescence-activated cell sorting for CD163 and FRβ expression as well as for messenger RNA (mRNA) expression of interleukin (IL)-10.ResultsOur in vivo study showed that intra-articular injections with TA strongly enhanced FRβ+ macrophage activation. Despite stimulated macrophage activation, osteophyte formation was fully prevented. There was no beneficial effect of TA against cartilage degradation or subchondral bone sclerosis. In vitro macrophage cultures showed that TA strongly induced monocyte differentiation towards CD163+ and FRβ+ macrophages. Furthermore, TA-stimulated M2 macrophages showed enhanced IL-10 expression at the mRNA level.ConclusionsTA injections potently induce a CD163+- and FRβ+-activated macrophage with anti-inflammatory characteristics such as reduced IL-10 production in vitro and lack of osteophytosis in vivo.

Amniotic Suspension Allograft Modulates Inflammation in a Rat Pain Model of Osteoarthritis

“…Another interesting finding in this study was increased subchondral bone sclerosis observed with triamcinolone treatment; this finding has been observed in previous in vivo and clinical studies . In this study, behavioral data suggests that triamcinolone exhibits an immediate effect, with significant differences compared with the vehicle control at 8–14 days, while ASA treatment shows a significant effect at 14 days that persists at 21 days.…”

Local controlled release of corticosteroids extends surgically induced joint instability by inhibiting tissue healing

“…While the weight of the animals receiving TAA bolus caught up with the weight of non‐treated animals 3 weeks post‐injection, extended release of TAA prevented this recovery, suggesting an extended systemic, though not detectable, presence of TAA. Weight loss in rats upon systemic oral exposure (Caparroz‐Assef, Bersani‐Amado, Kelmer‐Bracht, Bracht, & Ishii‐Iwamoto, ) and after weekly IA injections with a cumulative dose of 1.1‐mg TAA (Siebelt et al, ) was described before. This is in contrast to the weight gain through enhanced fluid retention and increased appetite found in human patients (Tataranni et al, ).…”

“…The aim of the current study was to evaluate the effects of biomate- Bracht, & Ishii-Iwamoto, 2007) and after weekly IA injections with a cumulative dose of 1.1-mg TAA (Siebelt et al, 2015) was described before. This is in contrast to the weight gain through enhanced fluid retention and increased appetite found in human patients (Tataranni et al, 1996).…”

Guiding synovial inflammation by macrophage phenotype modulation: an in vitro study towards a therapy for osteoarthritis

“…Although this subtype expressing CD163 has been described as the tissue repair phenotype 31 , is has also been associated with (chronic) inflammatory diseases 32,33 . Additionally, CD163 expressing macrophages induced by intra-articular injection of triamcinolone acetonide, also a corticosteroid, have been linked as well with the prevention of osteophyte formation in an OA rat model 34 .…”