Dynamic Change of Lumbar Structure and Associated Factors: A Retrospective Study.

OBJECTIVE: To determine whether lumbar anatomy parameters are in dynamic change and related factors. METHODS: This is a retrospective study. Participants who did lumbar computed tomography (CT) scanning in Shandong University Qilu Hospital from October 2017 to March 2019 were selected. The 476 participants were randomly selected as male or female, with the age ranging from 17 to 87 years (mean, 55.19; standard deviation, 14.28 years). All the measurements were taken based on the CT scanning image and the measurement of lumbar morphology was conducted using picture archiving and communication systems (PACS). The angle between the horizontal alignment and pedicle center on median sagittal view, the angle between upper endplate and lower endplate on median sagittal view as well as transverse section angle (TSA) using Magerl point in the axial view was determined by reconstructive CT analysis. RESULTS: In the overall participants, the angle between the horizontal alignment and pedicle center on median sagittal view of lumbar one to three was significantly decreased with aging, from 3.90° ± 2.81° to -4.18° ± 6.86° (P = 0.002), 5.60° ± 2.89° to -4.14° ± 5.90° (P = 0.030), and 4.75° ± 2.95° to -2.87° ± 4.68° (P < 0.001), respectively. Additionally, the angle between the horizontal alignment and pedicle center on median sagittal view in male participants of lumbar two was dramatically decreased, from 4.83° ± 2.79° to -4.45° ± 5.97° (P = 0.30). And that of lumbar three in female participants was significantly decreased, from 4.56° ± 2.52° to -2.88° ± 5.03° (P = 0.029). Furthermore, of the overall participants, the angle between upper endplate and lower endplate on median sagittal view of lumbar one to four was associated with aging (P < 0.001, P < 0.001, P = 0.015, P < 0.001, respectively). The angle of lumbar one, two and four in male participants and lumbar one to four in female participants were all significantly related to aging (all P < 0.05). Moreover, in the participants overall, the TSA of lumbar one to three was significantly associated with aging (P = 0.015, P = 0.006 and P = 0.007, respectively). In addition, this angle in lumbar one to lumbar four in male participants were all negatively associated with aging (P = 0.017, P = 0.001, P = 0.005 and P = 0.036, respectively). CONCLUSION: Lumbar anatomy parameters are in dynamic change in an age and gender dependent manner. During spine surgery in elderly patients, more attention should be paid to these anatomic changes.

Establishment of a Modified Collagen-Induced Arthritis Mouse Model to Investigate the Anti-inflammatory Activity of Progranulin in Inflammatory Arthritis.

Progranulin (PGRN) was found to play an anti-inflammatory and protective role in both inflammatory and degenerative arthritis (Tang et al., Science 332:478-484, 2011; Zhao et al., Ann Rheum Dis 74:2244-2253, 2015). We recently published a visualized protocol to demonstrate a surgically-induced mouse model for examining the protective role of PGRN in degenerative osteoarthritis (Zhao et al., J Vis Exp:e50924, 2014). Herein we describe a modified collagen-induced arthritis (CIA) mouse model to investigate the anti-inflammatory activity of PGRN in inflammatory arthritis. CIA model is the most commonly used autoimmune model of inflammatory arthritis which shares both immunological and pathological features with human rheumatoid arthritis. Autoimmune inflammatory arthritis is induced by immunization with an emulsion of complete Freund's adjuvant and chicken type II collagen (CII) using a modified procedure in PGRN deficient mice and control littermates. Using the protocol described here, the investigator should be able to reproducibly induce a high incidence of CIA in PGRN deficient mice and also learn how to critically evaluate the severity and incidence of this disease model.

Role of ADAMTS-12 in Protecting Against Inflammatory Arthritis in Mice By Interacting With and Inactivating Proinflammatory Connective Tissue Growth Factor.

OBJECTIVE: It has been reported that ADAMTS-12 is a susceptibility gene for rheumatoid arthritis (RA) development, and its level is significantly increased in RA patients. In addition, ADAMTS-12 is reported to be required for inflammation in otherwise healthy subjects. This study was undertaken to determine the role of ADAMTS-12 and the underlying mechanisms in the pathogenesis of inflammatory arthritis. METHODS: The collagen-induced arthritis (CIA) model was established in ADAMTS-12-deficient mice and their control littermates to determine the role of ADAMTS-12 in vivo. Micro-computed tomography scanning was used to demonstrate the destruction of the ankle joint; histologic analysis illustrated synovitis, pannus formation, and bone and cartilage destruction; enzyme-linked immunosorbent assay was performed to measure serum levels of inflammatory cytokines; and protein-protein interaction assays were performed to detect the interactions of ADAMTS-12 and its various deletion mutants with connective tissue growth factor (CTGF). RESULTS: Deficiency of ADAMTS-12 led to accelerated inflammatory arthritis in the CIA mouse model. Loss of ADAMTS-12 caused enhanced osteoclastogenesis. In vitro and in vivo protein-protein interaction assays demonstrated that ADAMTS-12 bound and processed CTGF, a previously unrecognized substrate of ADAMTS-12. In addition, deletion of ADAMTS-12 enhanced, while overexpression of ADMATS-12 reduced, CTGF-mediated inflammation. Furthermore, ADAMTS-12 regulation of inflammation was largely lost in CTGF-deficient macrophages. Importantly, blocking of CTGF attenuated elevated inflammatory arthritis seen in the ADAMTS-12-deficient CIA mouse model. CONCLUSION: This study provides evidence that ADAMTS-12 is a critical regulator of inflammatory arthritis and that this is mediated, at least in part, through control of CTGF turnover.

Progranulin derivative Atsttrin protects against early osteoarthritis in mouse and rat models.

BACKGROUND: Atsttrin, an engineered protein composed of three tumor necrosis factor receptor (TNFR)-binding fragments of progranulin (PGRN), shows therapeutic effect in multiple murine models of inflammatory arthritis . Additionally, intra-articular delivery of PGRN protects against osteoarthritis (OA) progression. The purpose of this study is to determine whether Atsttrin also has therapeutic effects in OA and the molecular mechanisms involved. METHODS: Surgically induced and noninvasive rupture OA models were established in mouse and rat, respectively. Cartilage degradation and OA were evaluated using Safranin O staining, immunohistochemistry, and ELISA. Additionally, expressions of pain-related markers, degenerative factors, and anabolic and catabolic markers known to be involved in OA were analyzed. Furthermore, the anabolic and anti-catabolic effects and underlying mechanisms of Atsttrin were determined using in-vitro assays with primary chondrocytes. RESULTS: Herein, we found Atsttrin effectively prevented the accelerated OA phenotype associated with PGRN deficiency. Additionally, Atsttrin exhibited a preventative effect in OA by protecting articular cartilage and reducing OA-associated pain in both nonsurgically induced rat and surgically induced murine OA models. Mechanistic studies revealed that Atsttrin stimulated TNFR2-Akt-Erk1/2-dependent chondrocyte anabolism, while inhibiting TNFα/TNFR1-mediated inflammatory catabolism. CONCLUSIONS: These findings not only provide new insights into the role of PGRN and its derived engineered protein Atsttrin in cartilage homeostasis as well as OA in vivo, but may also lead to new therapeutic alternatives for OA as well as other relative degenerative joint diseases.

Progranulin suppresses titanium particle induced inflammatory osteolysis by targeting TNFα signaling.

Aseptic loosening is a major complication of prosthetic joint surgery, characterized by chronic inflammation, pain, and osteolysis surrounding the bone-implant interface. Progranulin (PGRN) is known to have anti-inflammatory action by binding to Tumor Necrosis Factor (TNF) receptors and antagonizing TNFα. Here we report that titanium particles significantly induced PGRN expression in RAW264.7 cells and also in a mouse air-pouch model of inflammation. PGRN-deficiency enhanced, whereas administration of recombinant PGRN effectively inhibited, titanium particle-induced inflammation in an air pouch model. In addition, PGRN also significantly inhibited titanium particle-induced osteoclastogenesis and calvarial osteolysis in vitro, ex vivo and in vivo. Mechanistic studies demonstrated that the inhibition of PGRN on titanium particle induced-inflammation is primarily via neutralizing the titanium particle-activated TNFα/NF-κB signaling pathway and this is evidenced by the suppression of particle-induced IκB phosphorylation, NF-κB p65 nuclear translocation, and activity of the NF-κB-specific reporter gene. Collectively, these findings not only demonstrate that PGRN plays an important role in inhibiting titanium particle-induced inflammation, but also provide a potential therapeutic agent for the prevention of wear debris-induced inflammation and osteolysis.

Progranulin protects against osteoarthritis through interacting with TNF-α and ß-Catenin signalling.

OBJECTIVE: Progranulin (PGRN) was previously isolated as an osteoarthritis (OA)-associated growth factor. Additionally, PGRN was found to play a therapeutic role in inflammatory arthritis mice models through antagonising tumour necrosis factor α (TNF-α). This study was aimed at investigating the role of PGRN in degradation of cartilage and progression of OA. METHODS: Progression of OA was analysed in both spontaneous and surgically induced OA models in wild type and PGRN-deficient mice. Cartilage degradation and OA were evaluated using Safranin O staining, immunohistochemistry and ELISA. Additionally, mRNA expression of degenerative factors and catabolic markers known to be involved in cartilage degeneration in OA were analysed. Furthermore, the anabolic effects and underlying mechanisms of PGRN were investigated by in vitro experiments with primary chondrocytes. RESULTS: Here, we found that deficiency of PGRN led to spontaneous OA-like phenotype in 'aged' mice. Additionally, PGRN-deficient mice exhibited exaggerated breakdown of cartilage structure and OA progression, while local delivery of recombinant PGRN protein attenuated degradation of cartilage matrix and protected against OA development in surgically induced OA models. Furthermore, PGRN activated extracellular signal-regulated kinases (ERK) 1/2 signalling and elevated the levels of anabolic biomarkers in human chondrocyte, and the protective function of PGRN was mediated mainly through TNF receptor 2. Additionally, PGRN suppressed inflammatory action of TNF-α and inhibited the activation of ß-Catenin signalling in cartilage and chondrocytes. CONCLUSIONS: Collectively, this study provides new insight into the pathogenesis of OA, and also presents PGRN as a potential target for the treatment of joint degenerative diseases, including OA.