Lumican is upregulated in osteoarthritis and contributes to TLR4-induced pro-inflammatory activation of cartilage degradation and macrophage polarization

Abstract

Objective: Lumican (LUM) is a major extracellular matrix glycoprotein in adult articular cartilage and its expression is known to be upregulated upon cartilage degeneration. LUM is associated with the pathogen-associated molecular pattern (PAMP) activation of the TLR4 signalling cascade, with TLR4 being highly associated with inflammation in rheumatic diseases. However, the main role of the LUM structural molecule in osteoarthritis (OA) remains elusive. The aim of this study was, therefore, to understand the role of LUM during TLR4-mediated activation in OA. Methods: After measuring LUM levels in synovial fluid (SF) of OA patients and lipopolysaccharide (LPS)induced TLR4 activation, the role of LUM in the expression of pro-inflammatory molecules and cartilage degradation was assessed in vitro and ex vivo in a cartilage explant model. Primary macrophage activation and polarization were studied upon LUM co-stimulation with LPS. Results: We demonstrate that LUM is not only significantly upregulated in SF from OA patients compared to healthy controls, but also that LUM increases lipopolysaccharide (LPS)-induced TLR4 activation. Furthermore, we show that a pathophysiological level of LUM augments the LPS-induced TLR4 activation and expression of downstream pro-inflammatory molecules, resulting in extensive cartilage degradation. LUM co-stimulation with LPS also provided a pro-inflammatory stimulus, upregulating primary macrophage activation and polarization towards the M1-like phenotype. Conclusions: These findings strongly support the role of LUM as a mediator of PAMP-induced TLR4 activation of inflammation, cartilage degradation, and macrophage polarization in the OA joint and potentially other rheumatic diseases.

An Emerging Target in the Battle against Osteoarthritis: Macrophage Polarization

“…At the pathophysiological level , LUM promotes LPS-induced TLR4 activation, which finally leads to extensive cartilage degradation. Besides, the co-stimulation of LUM and LPS also promotes macrophage activation and causes polarization towards the M1 phenotype [ 63 ].…”

“…Very recently, Barreto and colleagues demonstrated that intact LUM in synovial fluid enhances the LPS-induced inflammatory response in a TLR4-dependent manner, indicating that LUM may promote the formation of OA through this pathway [ 23 , 64 ]. In terms of signaling pathways , LUM significantly activates the NF-kB signaling pathway in macrophages in OA joints [ 63 ]. In summary, LUM exacerbates the process of inflammation by acting on macrophages in OA joints.…”

“… [ 59 ] Lumican (LUM) Human primary chondrocytes and macrophages NA NF-κB LUM+LPS induces the differentiation of macrophages into M1 type Preclinical stage/NA In the TLR4-mediated OA model, the expression of LUM is up-regulated, which promotes the formation of M1 macrophages and aggravates OA symptoms. [ 23 , 61 , 62 , 63 , 64 ] Bone morphogenetic protein 7 (BMP-7) Primary human monocytes Patients with osteoarthritis NA NA Preclinical stage/NA BMP-7 regulates the inflammatory state of joints by changing the phenotype of OA synovium (polarizing monocytes into M2 type). [ 16 ] Squid type II collagen (SCII) RAW264.7 cells; mouse chondrocytes Mouse OA model induced by anterior cruciate ligament transection (ACLT) and partial meniscus resection (pMMx) STAT6 Promote the conversion of M1 macrophages into M2 macrophages Preclinical stage/NA SCII improves the symptoms of OA by promoting the polarization of M2 macrophages.…”

Osteoarthritis year in review 2020: biology

“…A study conducted by Mahon and co-workers showed that basic calcium phosphate crystals cause an M1-like macrophage differentiation, accompanied with a shift towards glycolytic energy metabolism, which has been shown to control inflammatory macrophage functions [12,13]. Another study demonstrated that the cartilage extracellular matrix protein lumican was increased in the synovial fluid (SF) from OA patients and augmented LPS-induced TLR4 signaling, which associated with increased expression of M1-like and decreased expression of M2-like macrophage markers [14].…”

Articular Repair/Regeneration in Healthy and Inflammatory Conditions: From Advanced In Vitro to In Vivo Models

“…[ 62 ] Also, work by Haltmayer et al showed in a model using horse osteochondral explants, where OA was induced by partial thickness defect in presence of proinflammatory cytokines (TNF‐α and IL‐1β), that MMP and IL‐6 expression were increased upon OA induction, and coculture with synovial membranes increased nitric oxide levels indicating M1 synovial macrophage polarization and improving the similarity of the model to physiological OA. [ 63 ] Two recent studies used a human OA cartilage explant model to demonstrate that exposure to Lumican, a small leucine‐rich proteoglycan that the author found upregulated in OA patient serum, when combined with LPS could activate cartilage degradation, with loss of proteoglycans, downregulation of COL2, and surface fibrillation; [ 64 ] and that physiological compression could modulate the inflammatory microenvironment and ECM composition. [ 65 ]…”