Arthritis Research & Therapy最新文献

Background: Subchondral insufficiency fracture of the knee (SIFK) is a rare and rapidly progressing knee joint disease. The typical diagnostic finding of SIFK by magnetic resonance imaging (MRI) is a subchondral hypointense line around the bone marrow lesions (BMLs), which are also commonly observed in knee osteoarthritis (OA). Subchondral bone fracture and its repair reactions are implicated for SIFK. However, pathological changes of SIFK and BMLs and the mechanism by which SIFK is induced remain elusive. We aimed to examine characteristics of SIFK and OA by micro-computed tomography (micro-CT) and histology together with biomarker analysis.

Methods: Nineteen patients with femoral or tibial SIFK (10 F-SIFK and 9 T-SIFK patients) and 24 knee OA patients, who were diagnosed by radiography and MRI and underwent unicompartmental knee arthroplasty, were enrolled for this study, and their medial tibial plateaus were examined by micro-CT and pathology. Serum and urine biomarkers were also analyzed.

Results: All the T-SIFK patients showed BMLs with a subchondral hypointense line by MRI. Micro-CT analysis revealed that the T-SIFK lesion comprises multiple subchondral bone fragments covered with articular cartilage. Histologically, the lesion was composed of articular cartilage-covered subchondral bone fragments, debris of bone and bone marrow, fibrogranulation tissue, cartilage and woven bone. The medial tibial plateaus from OA patients frequently exhibited eburnation, which was commonly accompanied by microfracture. All the BMLs observed in T-SIFK and OA were associated with fat necrosis, which was characterized by disrupted fat cells and foamy macrophage infiltration. The posterior tibial slope angle (12.84 ± 2.34° vs 9.58 ± 2.84°) and the rate of medial meniscal posterior root tears (68.4% vs 25.0%) were significantly higher in T-SIFK than OA. Numbers of grade 2 subchondral bone resorption pits in uninvolved areas of the medial tibial plateaus (2.32 ± 1.43 vs 0.72 ± 0.66) and the femoral condyles (5.53 ± 3.73 vs 1.50 ± 2.10) were significantly higher in T-SIFK than OA.

Conclusions: Our data demonstrate that T-SIFK is generated by subchondral bone fracture and its repair reaction and suggest that fat necrosis of the bone marrow is involved in BML formation in T-SIFK and OA.

Background: Subchondral bone is a dynamic tissue maintained by bone remodeling and responded rapidly to mechanical loading, which is strongly associated with cartilage degradation in osteoarthritis (OA), but the underlying mechanisms of which is still blurring.

Methods: Experimental OA mice models were generated by mechanical overload with 60 cycles of 14 N axial compressive loads twice a week or anterior cruciate ligament transection surgery. FSCN1 expression was evaluated in subchondral bone from experimental OA mice and human OA. Mice with FSCN1 conditional knockout in pre-osteoblasts were generated, and adeno-associated virus expressing FSCN1 was injected intra-articularly in mice. Therapeutic efficacy of FSCN1 inhibitor NP-G2-044 was determined in OA mice.

Results: Increased FSCN1 expression was positively associated with osteogenesis and subchondral bone sclerosis induced by mechanical loading. Deletion of FSCN1 in pre-osteoblasts delays osteogenesis and prevents abnormal subchondral bone sclerosis, whereas overexpression of FSCN1 exacerbates this. Under the stimulation of mechanical stress, Ras homologue gene family member A in osteoblasts competitively binds with protein kinase C to FSCN1, thereby inhibiting FSCN1 phosphorylation and promoting cytoskeleton formation, thereby activating Hippo/YAP signaling to increase metabolic activity of osteoblasts. These abnormal osteoblasts secrete more osteogenesis proteins, including osteopontin, leading to subchondral bone sclerosis and cartilage erosion, thus aggravating the progression of OA. Furthermore, we confirmed that the inhibitor of FSCN1, NP-G2-044 effectively attenuates subchondral bone sclerosis and OA progression in mice.

Conclusions: This study suggests that FSCN1 is a key factor in the relationship between mechanical stress, actin cytoskeleton dynamic, subchondral bone sclerosis and OA pathology. Targeting FSCN1 represents a promising pharmacological approach for OA therapy.

Background: There is an unmet clinical need to manage heart failure with preserved ejection fraction in people with rheumatoid arthritis (RA). One hurdle is the absence of preclinical models to study pathology and pharmacology in settings of inflammatory arthritis. In addition, there is mixed clinical evidence on the effect of current RA therapeutics, such as anti-interleukin-6 (IL-6) therapy, on the incidence of diastolic dysfunction and heart failure in RA patients.

Methods: We have used a transgenic mouse model (K/BxN F1 colony) where inflammatory arthritis develops prior to cardiac dysfunction. Polyarthritis was scored and paw volumes measured by plethysmometry. Heart functionality was assessed by echocardiography and plasma IL-6 was measured by ELISA. An anti-IL-6 receptor monoclonal antibody, MR16-1, was given after joint disease onset. Cardiac cell numbers were quantified by flow cytometry, along with phenotypic characterization of monocytes, macrophages and fibroblasts. In addition, the expression of selected inflammatory genes was quantified by qPCR.

Results: K/BxN F1 mice displayed higher IL-6 plasma levels than control mice, specifically after joint disease onset and prior to overt alterations in cardiac function. Treatment of arthritic K/BxN F1 male and female mice with MR16-1 resulted in a modest reduction (~ 15%) in joint disease whereas the development of diastolic dysfunction (monitored as left atrial area, E/A and e'/a' ratios) was prevented. These functional improvements in the heart were accompanied by a significant reduction in pro-inflammatory gene expression (e.g., Il1, Il6), decreased recruitment of classical monocytes (CCR2⁺Ly6C⁺), a lower number of pro-inflammatory macrophages (Gal-3⁺MHCII⁺CD206⁻), and reduced presence of pro-inflammatory cardiac fibroblasts (Thy1.2⁺podoplanin⁺).

Conclusions: Treatment of arthritic mice with an antibody that blocks IL-6 signalling is effective in preventing functional alterations of the heart, likely consequent to regulation of monocyte recruitment, and reductions in numbers of pro-inflammatory macrophages and fibroblasts. These preclinical data could prompt specific studies to determine the efficacy of anti-IL-6 therapy in patients at increased risk of cardiac alterations that lead to heart failure.