Objective Inflammation in the bone microenvironment stimulates osteoclast differentiation, resulting in uncoupling of resorption and formation. Mechanisms contributing to the inhibition of osteoblast function in inflammatory diseases, however, have not been elucidated. Rheumatoid arthritis (RA) is a prototype of an inflammatory arthritis that results in focal loss of articular bone. The paucity of bone repair in inflammatory diseases such as RA raises compelling questions regarding the impact of inflammation on bone formation. The aim of this study was to establish the mechanisms by which inflammation regulates osteoblast activity. Methods We characterized an innovative variant of a murine model of arthritis in which inflammation is induced in C57BL/6J mice by transfer of arthritogenic K/B×N serum and allowed to resolve. Results In the setting of resolving inflammation, bone resorption ceased and appositional osteoblast-mediated bone formation was induced, resulting in repair of eroded bone. Resolution of inflammation was accompanied by striking changes in the expression of regulators of the Wnt/β-catenin pathway, which is critical for osteoblast differentiation and function. Down-regulation of the Wnt antagonists secreted frizzled-related protein 1 (sFRP1) and sFRP2 during the resolution phase paralleled induction of the anabolic and pro–matrix mineralization factors Wnt10b and DKK2, demonstrating the role of inflammation in regulating Wnt signaling. Conclusion Repair of articular bone erosion occurs in the setting of resolving inflammation, accompanied by alterations in the Wnt signaling pathway. These data imply that in inflammatory diseases that result in persistent articular bone loss, strict control of inflammation may not be achieved and may be essential for the generation of an anabolic microenvironment that supports bone formation and repair.

Articular bone erosion in rheumatoid arthritis (RA) is mediated by the interaction between inflammation and pathways regulating bone metabolism. Inflammation promotes osteoclastogenesis and also inhibits osteoblast function, further contributing to the persistence of erosions. MicroRNAs (miRNAs) are important regulators of skeletal remodeling and play a role in RA pathogenesis. We therefore determined the expression of miRNAs in inflamed synovial tissue and the role they play in pathways regulating osteoblast and osteoclast function. Using the serum transfer mouse model of RA in C57BL/6 mice, we performed Fluidigm high-throughput qPCR-based screening of miRNAs from nonarthritic and arthritic mice. Global gene expression profiling was also performed on Affymetrix microarrays from these same synovial samples. miRNA and mRNA expression profiles were subjected to comparative bioinformatics. A total of 536 upregulated genes and 417 downregulated genes were identified that are predicted targets of miRNAs with reciprocal expression changes. Gene ontology analysis of these genes revealed significant enrichment in skeletal pathways. Of the 22 miRNAs whose expression was most significantly changed (p <0.01) between nonarthritic and arthritic mice, we identified their targets that both inhibit and promote bone formation. These miRNAs are predicted to target Wnt and BMP signaling pathway components. We validated miRNA array findings and demonstrated that secretion of miR-221-3p in exosomes was upregulated by synovial fibroblasts treated with the proinflammatory cytokine TNF. Overexpression of miR-221-3p suppressed calvarial osteoblast differentiation and mineralization in vitro. These results suggest that miRNAs derived from inflamed synovial tissues may regulate signaling pathways at erosion sites that affect bone loss and potentially also compensatory bone formation.

ObjectivesThe purpose of this work was to test whether normal peri-entheseal vascular anatomy at anterior and posterior cruciate ligaments (ACL and PCL) was associated with distribution of peri-entheseal bone erosion/bone marrow lesions (BMLs) in inflammatory arthritis (IA) and osteoarthritis (OA).MethodsNormal microanatomy was defined histologically in mice and by 3 T MRI and histology in 21 cadaveric knees. MRI of 89 patients from the Osteoarthritis Initiative and 27 patients with IA was evaluated for BMLs at ACL and PCL entheses. Antigen-induced arthritis (AIA) in mice was evaluated to ascertain whether putative peri-entheseal vascular regions influenced osteitis and bone erosion.ResultsVascular channels penetrating cortical bone were identified in knees of non-arthritic mice adjacent to the cruciate ligaments. On MRI of normal cadavers, vascular channels adjacent to the ACL (64% of cases) and PCL (71%) entheses were observed. Histology of 10 macroscopically normal cadaveric specimens confirmed the location of vascular channels and associated subclinical changes including subchondral bone damage (80% of cases) and micro-cyst formation (50%). In the AIA model, vascular channels clearly provided a site for inflammatory tissue entry and osteoclast activation. MRI showed BMLs in the same topographic locations in both patients with early OA (41% ACL, 59% PCL) and IA (44%, 33%).ConclusionThe findings show that normal ACL and PCL entheses have immediately adjacent vascular channels which are common sites of subtle bone marrow pathology in non-arthritic joints. These channels appear to be key determinants in bone damage in inflammatory and degenerative arthritis.

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Background We noted in mouse models of inflammatory arthritis (IA) that an early point of entry of inflammation into the marrow space occurs at sites where penetrating vessels entered the bone. The role of penetrating vessels in erosion formation in man has not been explored in IA, nor has the role of vascular channels in bone oedema in osteoarthritis (OA) been explored. Objectives The purpose of this work was to investigate the frequency of bone erosion and oedema in inflammatory and degenerative arthropathies in close proximity to the peri-entheseal ACL and PCL vascular channels. Methods Normal microanatomy was defined in 21 cadaveric knees using 3T MRI and histology. MRI of 89 patients from the Osteoarthritis Initiative study and 27 patients with inflammatory arthritis were evaluated for erosion and bone oedema at the same locations. Two animal models of inflammatory arthritis were evaluated to ascertain whether the putative peri-entheseal vascular regions influenced the propensity of osteitis and bone erosion. Results Data from the two animal models of IA showed inflammation entering the marrow space along the adventitia of blood vessels that penetrate the cortical bone in close proximity to the cruciate ligament insertions. On 3T MRI, a vascular channel adjacent to the ACL tibial insertion was observed in 64% of cadaveric specimens examined. Similarly, a vascular channel adjacent to the PCL was seen in 71% of cases. Bone marrow oedema was observed in the regions corresponding to the location of the vascular channel in 51% of knees for both the anterior and posterior channel. Histological evaluation of 10 cadaveric specimens confirmed the location of the vascular channels along with the presence of associated subclinical microdamage including subchondral bone erosion (80% of cases) and micro-cyst formation (50%). Evaluation of patient MRIs showed the prevalence of oedematous features in the same topographic locations in patients with early OA (41% ACL, 59% PCL) and inflammatory arthritis (44% ACL, 33% PCL), (figure 1 ). Image/graph Conclusions Our findings show that the vascular channels adjacent to the anterior and posterior cruciate ligament entheses are common locations for erosion formation and damage in both inflammatory and degenerative arthritis. Furthermore, we have found a significant clustering of subclinical microdamage in these regions in normal cadaveric samples. Therefore, we conclude that peri-entheseal vascular channels are likely to present a common pathogenesis focus for both OA and IA. Disclosure of Interest None Declared