Extracellular PPM1A promotes mineralization of osteoblasts differentiation in ankylosing spondylitis via the FOXO1A-RUNX2 pathway.

Protein phosphatase magnesium-dependent 1A (PPM1A), serine/threonine protein phosphatase, in sera level was increased in patients with ankylosing spondylitis (AS). Preosteoblasts were differentiated actively to matured osteoblasts by intracellular PPM1A overexpression. However, it was unclear whether extracellular PPM1A contributes to the excessive bone-forming activity in AS. Here, we confirmed that PPM1A and runt-related transcription factor 2 (RUNX2) were increased in facet joints of AS. During osteoblasts differentiation, exogenous PPM1A treatment showed increased matrix mineralization in AS-osteoprogenitor cells accompanied by induction of RUNX2 and factor forkhead box O1A (FOXO1A) protein expressions. Moreover, upon growth condition, exogenous PPM1A treatment showed an increase in RUNX2 and FOXO1A protein expression and a decrease in phosphorylation at ser256 of FOXO1A protein in AS-osteoprogenitor cells, and positively regulated promoter activity of RUNX2 protein-binding motif. Mechanically, exogenous PPM1A treatment induced the dephosphorylation of transcription factor FOXO1A protein and translocation of FOXO1A protein into the nucleus for RUNX2 upregulation. Taken together, our results suggest that high PPM1A concentration promotes matrix mineralization in AS via the FOXO1A-RUNX2 pathway.

Clinical and genetic factors associated with radiographic damage in patients with ankylosing spondylitis.

OBJECTIVES: To identify clinical and genetic factors associated with severe radiographic damage in patients with ankylosing spondylitis (AS). METHODS: We newly generated genome-wide single nucleotide polymorphism data (833K) for 444 patients with AS. The severity of radiographic damage was assessed using the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS). To identify clinical and genetic factors associated with severe radiographic damage, multiple linear regression analyses were performed. Human AS-osteoprogenitor and control-osteoprogenitor cells were used for functional validation. RESULTS: The significant clinical factors of final mSASSS were baseline mSASSS (ß=0.796, p=3.22×10-75), peripheral joint arthritis (ß=-0.246, p=6.85×10-6), uveitis (ß=0.157, p=1.95×10-3), and smoking (ß=0.130, p=2.72×10-2) after adjusting for sex, age and disease duration. After adjusting significant clinical factors, the Ryanodine receptor 3 (RYR3) gene was associated with severe radiographic damage (p=1.00×10-6). For pathway analysis, the PI3K-Akt signalling pathway was associated with severe radiographic damage in AS (p=2.21×10-4, false discovery rate=0.040). Treatment with rhodamine B, a ligand of RYR3, dose-dependently induced matrix mineralisation of AS osteoprogenitors. However, the rhodamine B-induced accelerated matrix mineralisation was not definitive in control osteoprogenitors. Knockdown of RYR3 inhibited matrix mineralisation in SaOS2 cell lines. CONCLUSIONS: This study identified clinical and genetic factors that contributed to better understanding of the pathogenesis and biology associated with radiographic damage in AS.

STAT3 phosphorylation inhibition for treating inflammation and new bone formation in ankylosing spondylitis.

OBJECTIVE: AS is a rheumatic disease characterized by chronic inflammation and bony ankylosis. This study was to evaluate whether a signal transducer and activator of transcription 3 phosphorylation inhibitor (stat3-p Inh) could treat both chronic inflammation and bone formation in AS. METHODS: Primary AS osteoprogenitor cells and spinal entheseal cells were examined for osteogenic differentiation. SF mononuclear cells (SFMCs) and lamina propria mononuclear cells (LPMCs) were obtained from AS patients. Inflammatory cytokine-producing cells were analysed using flow cytometry and ELISA. Female SKG mice were treated with stat3-p Inh, IL-17A blocker or vehicle. Inflammation and new bone formation were evaluated using immunohistochemistry, PET and micro-CT. RESULTS: In the SKG mouse model, stat3-p Inh significantly suppressed arthritis, enthesitis, spondylitis and ileitis. In experiments culturing SFMCs and LPMCs, the frequencies of IFN-γ-, IL-17A- and TNF-α-producing cells were significantly decreased after stat3-p Inh treatment. When comparing current treatments for AS, stat3-p Inh showed a comparable suppression effect on osteogenesis to Janus kinase inhibitor or IL-17A blocker in AS-osteoprogenitor cells. Stat3-p Inh suppressed differentiation and mineralization of AS-osteoprogenitor cells and entheseal cells toward osteoblasts. Micro-CT analysis of hind paws revealed less new bone formation in stat3-p Inh-treated mice than vehicle-treated mice (P = 0.005). Hind paw and spinal new bone formation were similar between stat3-p Inh- and anti-IL-17A-treated SKG mice (P = 0.874 and P = 0.117, respectively). CONCLUSION: Stat-3p inhibition is a promising treatment for both inflammation and new bone formation in AS.

Sarcopenia and fatty degeneration of paraspinal muscle associated with increased sagittal vertical axis in the elderly: a cross-sectional study in 71 female patients.

PURPOSE: Both increased sagittal vertical axis (SVA) and sarcopenia affect performance of daily activities and morbidity in the elderly; however, little is known regarding their relationship. The aim of this study was to analyze the association between sarcopenia and increased SVA. METHODS: This retrospective study included 71 female patients aged between 60 and 85 years. Entire-spine radiography was used to measure radiological parameters. A bioelectrical impedance analyzer was used to measure the skeletal muscle mass index (SMI). Gait velocity (GV) and hand grip strength (HGS) were examined as well. Lumbar spine magnetic resonance imaging was employed to measure the functional cross-sectional area (FCSA) and fat signal fraction (FSF) of the paraspinal muscle as well. The subjects were divided into two groups according to the SVA (group I; SVA > 50 mm and group II; SVA ≤ 50 mm). RESULTS: The group I showed lower GV, HGS, and SMI than the group II (p < 0.001, < 0.001, and = 0.001, respectively). The prevalence of sarcopenia was higher in the group I (56.7%) than in the group II (17.1%) (p = 0.001). The group I also showed lower FCSA and higher FSF than the group II (p < 0.001). In multivariate analysis, the FSF (odds ratio 1.308, p = 0.004) and HGS (odds ratio 0.792, p = 0.023) were correlated with increased SVA. In addition, the BMI (odds ratio 0.756, p = 0.037), SVA (odds ratio 1.051, p = 0.031), and FCSA (odds ratio 0.995, p = 0.012) were correlated with sarcopenia. CONCLUSION: Sarcopenia and fatty degeneration of paraspinal muscle are closely related to increased SVA in the elderly.

Acetabular cup migration after primary cementless total hip arthroplasty in rheumatoid arthritis and its influencing factors: a comparative study with osteoarthritic hip.

PURPOSE: To compare the radiographic migration profiles of primary cementless total hip arthroplasty (THA) between patients with rheumatoid arthritis (RA) and those with osteoarthritis (OA). METHODS: A total of 197 patients (215 hips) who underwent cementless THA for RA or OA between January 2001 and January 2013 and followed up for a minimum of 5.5 years were included. Ninety-four RA patients (109 hips) were compared with 103 OA patients (106 hips). Radiological evaluation was performed for acetabular cup loosening, and cup migration was measured using Einzel-Bild-Röntgen-Analyse (EBRA) software. Multiple variables were assessed to identify influencing factors for cup migration. RESULTS: Early cup migration was observed in 13 hips (11.9%) in the RA group and four hips (3.8%) in the OA group, showing a significant difference (p = 0.041). Acetabular cup loosening occurred in three cups (2.8%) in the RA group and in one cup (0.9%) in the OA group, showing no significant difference (p = 0.321). Total cup migration was higher in the RA group (2.62 mm) than in the OA group (1.44 mm, p = 0.005). Total cup migration was significantly higher in patients aged < 50 years than in those aged > 50 years (p = 0.005). Rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) antibody influenced total cup migration. Patients with seropositive RA showed significantly higher total cup migration and early cup migration incidence than those with seronegative RA (p = 0.005, p = 0.038, respectively). CONCLUSIONS: Acetabular cups in primary cementless THAs of RA patients were less stable in terms of cup migration compared with that of OA patients.

Identification and characterization of human bone-derived cells.

This study was designed to identify and characterize primary bone-derived cells (BdCs) and investigate the potential role of osteoblast differentiation. Primary BdCs were isolated from surgical bone for comparative analysis with mesenchymal stem cells (MSCs) and fetal osteoblasts (FOBs) and for potential differentiation to mature osteoblasts. Using three different cells, we successfully cultivated human osteoblast differentiation and activity which were evaluated using microarray and biochemical methods. BdCs are more correlated to MSCs in bioinformatics result and similar with FOBs in gene expression. In particular, Osterix, osteoprogenitor marker, was high expressed in BdCs, while the expression in MSCs and FOBs were very low. Furthermore, BdCs exhibited a marked alkaline phosphatase (ALP) expression, early stage of osteogenic marker, and retained osteogenic properties and physiological changes into maturation as in FOBs. BdCs also showed an increase in bone morphogenic protein 2 (BMP2), osteopontin (OPN), and osteocalcin (OCN) mRNA expressions during differentiation. This study suggests that BdCs may be osteoprogenitor cells or undifferentiated preosteoblasts with strong capacity to differentiate toward mature osteoblasts.

Accelerated osteogenic differentiation of human bone-derived cells in ankylosing spondylitis.

Ankylosing spondylitis (AS) is characterized by excessive bone formation with syndesmophytes, leading to bony ankylosis. The contribution of osteoblasts to the pathogenesis of ankylosis is poorly understood. The aim of this study was to determine molecular differences between disease controls (Ct) and AS bone-derived cells (BdCs) during osteogenic differentiation with or without inflammation using AS patient serum. We confirmed osteoblastic differentiation of Ct and AS BdCs under osteogenic medium by observing morphological changes and measuring osteoblastic differentiation markers. Osteoblast differentiation was detected by alkaline phosphatase (ALP) staining and activity, and alizarin red and hydroxyapatite staining. Osteoblast-specific markers were analyzed by quantitative reverse-transcriptase-polymerase chain reaction, immunoblotting, and immunostaining. To examine the effects of inflammation, we added AS and healthy control serum to Ct and AS BdCs, and then analyzed osteoblast-specific markers. AS BdCs showed elevated basal intercellular and extracellular ALP activity compared to Ct. When osteoblast differentiation was induced, AS BdCs exhibited higher expression of osteoblast-specific marker genes and faster mineralization than Ct, indicating that these cells differentiated more rapidly into osteoblasts. ALP activity and mineralization accelerated when serum from AS patients was added to Ct and AS BdCs. Our results revealed that AS BdCs showed significantly increased osteoblastic activity and differentiation capacity by regulating osteoblast-specific transcription factors and proteins compared to Ct BdCs. Active inflammation of AS serum accelerated osteoblastic activity. Our study could provide useful basic data for understanding the molecular mechanism of ankylosis in AS.

Intra-cardiac Embolism of a Large Bone Cement Material after Percutaneous Vertebroplasty Removed through a Combination of an Endovascular Procedure and an Inferior Vena Cava Exploration: a Case Report.

Percutaneous vertebroplasty (PVP) is a minimally invasive surgical treatment for patients with osteoporotic vertebral compression fracture (OVCF) and can rapidly alleviate pain, improve mobility, and stabilize the vertebrae. However, it has the potential to cause complications such as cement embolism. A 55-year-old female presented with pain in the lumbar region as a chief complaint. PVP was performed after diagnosis of acute OVCFs at L4 and L5. No abnormal symptoms were reported after surgery, but a large cement embolism was observed in her right atrium and ventricle. After discussion in a multi-disciplinary team, the large cement embolism was successfully removed by a combination of endovascular procedure and an inferior vena cava exploration. Surgeons must consider the possibility of intra-cardiac cement embolism after PVP. A hybrid approach of an endovascular procedure and a vascular surgery may be a reasonable treatment option to minimize the surgical procedure in cases of a large intra-cardiac cement embolism.

A novel role for bone-derived cells in ankylosing spondylitis: Focus on IL-23.

The main aim of this study are to explore the role of bone-derived cells (BdCs) in ankylosing spondylitis (AS) and determine the underlying molecular mechanisms of IL-23 production. Primary BdCs were isolated from diced bone of facet joints obtained during surgery from seven AS patients and seven disease control (Ct) patients. Osteoblastic activity of BdCs was assessed by measuring their alkaline phosphatase activity and by alizarin red staining. Osteoblast and endoplasmic reticulum (ER) stress-related genes were assessed by quantitative PCR, immunoblotting, immunofluorescence, and immunohistochemistry. In addition, expression of IL-23 in response to BIX (selective BIP inducer X)-induced ER stress was evaluated by qPCR and ELISA. Protein interaction and binding to IL-23 promoter were confirmed by Immunoprecipitation and Chromatin immunoprecipitation, respectively. Transcript levels of genes involved in osteoblast function, as well as of the ER stress marker were higher in the AS group than the Ct group, and elevated RUNX2, BiP and IL-23 expression were observed in the BdCs, serum, and bone biopsies from the AS group. BIX-induced ER stress stimulated osteoblastic activity and IL-23 secretion by upregulating RUNX2 expression. Furthermore, in AS BdCs, RUNX2 interacted with C/EBPß to bind to IL-23 promoter and RUNX2 knockdown suppressed IL-23 secretion. These finding may provide a molecular mechanism involved in sustained ER stress in AS BdCs stimulates the activation of RUNX2 and C/EBPß genes, leading to IL-23 production.

Is It Possible to Increase the Clinical Effectiveness of the Fracture Risk Assessment Tool in Osteopenia Patients by Taking Into Account Bone Mineral Density Values?

The study aimed to investigate the effectiveness of the clinical use of the Fracture Risk Assessment Tool (FRAX(®)) developed by the World Health Organization identifying patients at risk of osteoporotic fracture and to evaluate changes in osteoporotic fracture risk prediction according to bone mineral density (BMD) values. We identified the occurrence of osteoporotic fracture among patients whose BMD was measured in our hospital between April 2003 and March 2013. We then analyzed FRAX(®) scores obtained with or without BMD on the day before the occurrence of an osteoporotic fracture in actual osteoporotic fracture patients. According to the National Osteoporosis Foundation high-risk criteria, we identified the percentage of high-risk patients before the actual fracture. Among 445 osteoporotic fracture patients, when FRAX(®)-BMD was used, 281 patients (63%) were identified as high-risk before an actual osteoporotic fracture, and when FRAX(®) without BMD was used, 258 patients (58%) were identified (p = 0.115). In the 84 osteopenia patients, 39 patients (46.4%) were identified as high-risk when FRAX(®) without BMD was used, and 19 patients (22.6%) were identified when FRAX(®)-BMD was used (p = 0.001). The use of BMD in FRAX(®) does not seem to increase the clinical effectiveness of predicting osteoporotic fracture in osteopenia patients.

The complement factor H-related protein-5 (CFHR5) exacerbates pathological bone formation in ankylosing spondylitis.

Ankylosing spondylitis (AS) is a chronic inflammatory disease, characterized by excessive new bone formation. We previously reported that the complement factor H-related protein-5 (CFHR5), a member of the human factor H protein family, is significantly elevated in patients with AS compared to other rheumatic diseases. However, the pathophysiological mechanism underlying new bone formation by CFHR5 is not fully understood. In this study, we revealed that CFHR5 and proinflammatory cytokines (TNF, IL-6, IL-17A, and IL-23) were elevated in the AS group compared to the HC group. Correlation analysis revealed that CFHR5 levels were not significantly associated with proinflammatory cytokines, while CFHR5 levels in AS were only positively correlated with the high CRP group. Notably, treatment with soluble CFHR5 has no effect on clinical arthritis scores and thickness at hind paw in curdlan-injected SKG, but significantly increased the ectopic bone formation at the calcaneus and tibia bones of the ankle as revealed by micro-CT image and quantification. Basal CFHR5 expression was upregulated in AS-osteoprogenitors compared to control cells. Also, treatment with CFHR5 remarkedly induced bone mineralization status of AS-osteoprogenitors during osteogenic differentiation accompanied by MMP13 expression. We provide the first evidence demonstrating that CFHR5 can exacerbate the pathological bone formation of AS. Therapeutic modulation of CFHR5 could be promising for future treatment of AS. KEY MESSAGES: Serum level of CFHR5 is elevated and positively correlated with high CRP group of AS patients. Recombinant CFHR5 protein contributes to pathological bone formation in in vivo model of AS. CFHR5 is highly expressed in AS-osteoprogenitors compared to disease control. Recombinant CFHR5 protein increased bone mineralization accompanied by MMP13 in vitro model of AS.

HIF-1α and MIF enhance neutrophil-driven type 3 immunity and chondrogenesis in a murine spondyloarthritis model.

The hallmarks of spondyloarthritis (SpA) are type 3 immunity-driven inflammation and new bone formation (NBF). Macrophage migration inhibitory factor (MIF) was found to be a key driver of the pathogenesis of SpA by amplifying type 3 immunity, yet MIF-interacting molecules and networks remain elusive. Herein, we identified hypoxia-inducible factor-1 alpha (HIF1A) as an interacting partner molecule of MIF that drives SpA pathologies, including inflammation and NBF. HIF1A expression was increased in the joint tissues and synovial fluid of SpA patients and curdlan-injected SKG (curdlan-SKG) mice compared to the respective controls. Under hypoxic conditions in which HIF1A was stabilized, human and mouse neutrophils exhibited substantially increased expression of MIF and IL-23, an upstream type 3 immunity-related cytokine. Similar to MIF, systemic overexpression of IL-23 induced SpA pathology in SKG mice, while the injection of a HIF1A-selective inhibitor (PX-478) into curdlan-SKG mice prevented or attenuated SpA pathology, as indicated by a marked reduction in the expression of MIF and IL-23. Furthermore, genetic deletion of MIF or HIF1A inhibition with PX-478 in IL-23-overexpressing SKG mice did not induce evident arthritis or NBF, despite the presence of psoriasis-like dermatitis and blepharitis. We also found that MIF- and IL-23-expressing neutrophils infiltrated areas of the NBF in curdlan-SKG mice. These neutrophils potentially increased chondrogenesis and cell proliferation via the upregulation of STAT3 in periosteal cells and ligamental cells during endochondral ossification. Together, these results provide supporting evidence for an MIF/HIF1A regulatory network, and inhibition of HIF1A may be a novel therapeutic approach for SpA by suppressing type 3 immunity-mediated inflammation and NBF.

The analysis of spinopelvic parameters and stability following long fusions with S1, S2 or iliac fixation.

PURPOSE: The purpose of this study was to analyse changes of spinopelvic parameters and stability in the treatment of degenerative lumbar deformity. METHODS: A retrospective review was carried out on 70 cases of degenerative lumbar deformity treated by long fusion with uni-cortical S1 fixation alone (US1F group, n = 20), bi-cortical S1 fixation alone (BS1F group, n = 20), additional diagonal S2 fixation (DS2F group, n = 14), and additional iliac fixation (ILF group, n = 16) from July 2003 to April 2010. The sagittal vertical axis (SVA), lumbar lordosis (LL), sacral slope (SS), pelvic tilt (PT), pelvic incidence (PI), and stability were used to evaluate radiologic outcomes. The clinical outcome was evaluated using the Oswestry Disability Index (ODI). RESULTS: In all groups, the LL was significantly increased at three months (p < 0.05). The PI and the SS of ILF patients significantly increased at three months (p < 0.05), while none of these values changed over time in non-ILF patients. The PT did not change postoperatively in any groups. The LL, SS, and PI were significantly greater in the ILF group at three months postoperatively and later (p < 0.05). DS2F and ILF had statistically significant stability compared to US1F and BS1F (p < 0.05). The ODI scores were significantly improved after surgery in all groups compared to before surgery (p < 0.05). CONCLUSIONS: Patients who had ILF in long fusion for the treatment of degenerative lumbar deformity had significant restoration of spinopelvic parameters compared to the other groups. In addition, DS2F and ILF provided more stability of distal instruments.

Re-stooping after Corrective Osteotomy in Patients with Ankylosing Spondylitis.

Background: Corrective osteotomy is an effective surgery for correcting posture in patients with ankylosing spondylitis (AS). Despite satisfactory correction, some patients experience re-stooping during follow-up. However, there have been no studies on re-stooping in AS. We aimed to analyze the factors that affect re-stooping. Methods: Fifty patients (50 cases) who underwent thoracolumbar corrective osteotomy for AS from March 2006 to April 2018 were analyzed. We defined re-stooping as global kyphosis that recurs after corrective osteotomy. The patients were divided into two groups based on the ratio of correction loss: non-re-stooping group (N group) and re-stooping group (R group). We analyzed the demographic data and radiological parameters, such as modified Stoke Ankylosing Spondylitis Spine Score (mSASSS), sagittal vertical axis, and various angles. We also investigated the factors affecting re-stooping by analyzing the correlation between the ratio of correction loss and various factors. Results: A significant difference was seen in the change in the mSASSS from before surgery to the last follow-up between the N group (2.87 ± 3.08) and the R group (9.20 ± 5.44). In multivariate analysis, only the change in the mSASSS from before surgery to the last follow-up was significantly correlated with the ratio of correction loss. Conclusions: Thoracolumbar corrective osteotomy seems to provide high satisfaction among patients with AS but can lead to re-stooping during follow-up. The change in mSASSS was related with re-stooping in the current study. We recommend active rehabilitative exercises and appropriate medication depending on the patient's condition, which may help delay the postoperative progression of AS.

Elevated BMPR2 expression amplifies osteoblast differentiation in ankylosing spondylitis.

Objective: Bone morphogenetic protein receptor type 2 (BMPR2) has been associated with radiographic changes in ankylosing spondylitis (AS), but further characterization of the cellular signaling pathway in osteoprogenitor (OP) is not clearly understood. The aim of this study was to investigate the expression of BMPR2 and bone morphogenetic protein 2 (BMP2)-mediated responsibility in AS. Methods: We collected 10 healthy control (HC) and 14 AS-OPs derived from facet joints. Subsequently, we then conducted RNA sequencing with two samples per group and selected BMP-related genes. Facet joint tissues and derived primary OPs were evaluated by validation of selected RNA sequencing data, immunohistochemistry, and comparison of osteogenic differentiation potential. Results: Based on RNA-sequencing analysis, we found that BMPR2 expression is higher in AS-OPs compared to in HC-OPs. We also validated the increased BMPR2 expression in facet joint tissues with AS and its derived OPs in messenger RNA and protein levels. Additionally, primary AS-OPs showed much greater response to osteogenic differentiation induced by BMP2 and a higher capacity for smad1/5/8-induced RUNX2 expression compared to HCs. Conclusion: The expression of BMPR2 was found to be significantly increased in facet joint tissues of patients with AS. These findings suggest that BMPR2 may play a role in the BMP2-mediated progression of AS.

Angiotensin receptor blockers, but not angiotensin-converting enzyme inhibitors, inhibit abnormal bone changes in spondyloarthritis.

Spondyloarthritis (SpA) is a chronic inflammatory disease that results in bone ankylosis. The tissue renin-angiotensin system (RAS) is an emerging pathway potentially implicated in SpA-associated bone changes. The aim of the present study was to determine the mechanisms underlying this relationship. Sakaguchi (SKG) mice injected with curdlan (SKGc), animal models for SpA, were treated with RAS modulators, angiotensin II receptor blockers (ARBs) or angiotensin-converting enzyme inhibitors (ACEis). Disease activity was assessed using clinical scores and computed tomography scans. Mouse primary bone marrow monocytes (BMMs), osteoblast (OB) progenitor cells, peripheral blood monocytes (PBMCs), and bone-derived cells (BdCs) from patients with radiographic axial SpA (r-axSpA) were used to investigate the role of RAS in SpA pathogenesis. The expression of RAS components was significantly increased in SKGc mouse joints, and ARBs significantly reduced erosion and systemic bone loss, whereas ACEis did not. Osteoclast (OC) differentiation from primary BMMs, mediated by TRAF6, was inhibited by ARBs but promoted by ACEis; the modulators also exerted opposite effects on OB differentiation. Expression of RAS molecules was higher in PBMCs and BdCs of patients with r-axSpA than in control participants. ARBs inhibited OB differentiation in the BdCs of patients with r-axSpA, whereas ACEis did not. Neither ARBs nor ACEis affected OB differentiation in the control participants. In SpA, a condition characterized by RAS overexpression, ARBs, but not ACEis, inhibited OC and OB differentiation and bone progression. The findings should be taken into account when treating patients with SpA using RAS modulators.

Platelet-Derived Growth Factor B Is a Key Element in the Pathological Bone Formation of Ankylosing Spondylitis.

Enthesophyte formation plays a crucial role in the development of spinal ankylosis in ankylosing spondylitis (AS). We aimed to investigate the role of platelet-derived growth factor B (PDGFB) in enthesophyte formation of AS using in vitro and in vivo models and to determine the association between PDGFB and spinal progression in AS. Serum PDGFB levels were measured in AS patients and healthy controls (HC). Human entheseal tissues attached to facet joints or spinous processes were harvested at the time of surgery and investigated for bone-forming activity. The impact of a pharmacological agonist and antagonist of platelet-derived growth factor B receptor (PDGFRB) were investigated respectively in curdlan-treated SKG mice. PDGFB levels were elevated in AS sera and correlated with radiographic progression of AS in the spine. Mature osteoclasts secreting PDGFB proteins were increased in the AS group compared with HC and were observed in bony ankylosis tissues of AS. Expression of PDGFRB was significantly elevated in the spinous enthesis and facet joints of AS compared with controls. Moreover, recombinant PDGFB treatment accelerated bone mineralization of enthesis cells, which was pronounced in AS, whereas PDGFRB inhibition efficiently reduced the PDGFB-induced bone mineralization. Also, PDGFRB inhibition attenuated the severity of arthritis and enthesophyte formation at the joints of curdlan-treated SKG mice. This study suggests that regulating PDGFB/PDGFRB signaling could be a novel therapeutic strategy to block key pathophysiological processes of AS. © 2022 American Society for Bone and Mineral Research (ASBMR).

Biomechanical comparison of the femoral neck system and the dynamic hip screw in basicervical femoral neck fractures.

The purpose of this study was to compare the fixation stability of proximal fragments and the mechanical characteristics in proximal femur models of basicervical femoral neck fracture fixed by the femoral neck system (FNS) versus the dynamic hip screw. The mean axial stiffness was 234 ± 35 N/mm in the FNS group and 253 ± 42 N/mm in the DHS group, showing no significant difference (p = 0.654). Mean values for x-axis rotation, y-axis rotation, and z-axis rotation after cycle load were 2.2 ± 0.5°, 6.5 ± 1.5°, and 2.5 ± 0.6°, respectively, in the FNS group and 2.5 ± 0.7°, 5.8 ± 2.1°, and 2.2 ± 0.9°, respectively, in the DHS group, showing no significant differences (p = 0.324, p = 0.245, and p = 0.312, respectively). The mean values of cranial and axial migration of screws within the femoral head were 1.5 ± 0.3 and 2.1 ± 0.2 mm, respectively, in the FNS group and 1.2 ± 0.3 and 2.4 ± 0.3 mm, respectively, in the DHS group, showing no significant differences (p = 0.425 and p = 0.625, respectively). The average failure load at vertical load was 1342 ± 201 N in the FNS group and 1450 ± 196 N in the DHS group, showing no significant difference (p = 0.452). FNS fixation might provide biomechanical stability comparable to that of DHS for treating displaced basicervical femoral neck fractures in young adults.

Survival analysis and risk factors of new vertebral fracture after vertebroplasty for osteoporotic vertebral compression fracture.

BACKGROUND CONTEXT: Although risk factors of new adjacent vertebral fracture (AVF) and remote vertebral fracture (RVF) after vertebroplasty may differ, research on this topic is lacking. PURPOSE: To determine the natural course of new vertebral fractures after vertebroplasty for osteoporotic vertebral compression fracture (OVCF) and to analyze each risk factor for understanding the incidence of AVF and RVF. STUDY DESIGN: Retrospective cohort study. PATIENT SAMPLE: The study subjects included 205 patients who received vertebroplasty for OVCF and were followed-up for at least 1-year. OUTCOME MEASURES: Data on factors that could affect the occurrence of vertebral fractures, such as age, body mass index, and bone density, were collected from the patients' medical records. Fracture pattern, fracture location, sagittal imbalance, degree of segmental kyphosis after vertebroplasty, cement distribution, and cement leakage were radiologically examined. METHODS: xDuring the follow-up period, any newly developed vertebral fractures were identified. We analyzed whether the time of occurrence differed between AVF and RVF by performing a survival analysis and each risk factor separately. RESULTS: New vertebral fractures occurred in 47 patients (22.9%) after vertebroplasty, AVF occurred in 21 patients (10.2%), and RVF occurred in 26 patients (12.7%). The onset time of AVF was 6.2±1.8 months after vertebroplasty, showing a significant difference from that of RVF, which was 15.2±1.8 months (p<.001). In the univariate analysis, the risk factors of AVF included severe osteoporosis (T-score<-3.0), vertebroplasty in the thoracolumbar junction, sagittal imbalance, and segmental kyphosis angle >15° (p=0.029, p=0.033, p=0.001, and p=0.021, respectively). The risk factors of RVF included severe osteoporosis (T-score <-3.0) and sagittal imbalance (p=0.013 and p=0.004). In the multivariate analysis, the risk factors of AVF included vertebroplasty in the thoracolumbar junction and sagittal imbalance (hazard ratio=3.34, p=0.032 and hazard ratio=4.05, p=0.008), and those of RVF included only sagittal imbalance (hazard ratio=2.66, p=0.024). CONCLUSON: After vertebroplasty for OVCF, a significant difference in the meantime of occurrence was found; it took 6 months for AVF and 15 months for RVF to develop. Vertebroplasty in the thoracolumbar junction was identified as a risk factor for AVF, whereas sagittal imbalance was a risk factor of both AVF and RVF.

WNT16 elevation induced cell senescence of osteoblasts in ankylosing spondylitis.

BACKGROUND: WNT16 is critical for bone homeostasis, but the effect of WNT16 in ankylosing spondylitis (AS) is still unknown. Here, we investigated whether WNT16 influences bone formation and pathophysiological changes of AS in an in vitro model. METHODS: The bone tissue from the facet joints was obtained from seven disease control and seven AS patients. Primary osteoprogenitor cells of the facet joints were isolated using an outgrowth method. Isolated osteoprogenitor cells from both control and AS tissues were analyzed by microarray, RT-qPCR, immunoblotting, and immunohistochemistry. The bone-forming activity of osteoprogenitor cells was assessed by various in vitro assays. ß-galactosidase staining and senescence-associated secretory phenotype (SASP) using RT-qPCR were used to assess cell senescence. RESULTS: In microarray analysis, WNT16 expression was significantly elevated in AS osteoprogenitor cells compared to the control. We also validated that WNT16 expression was elevated in AS-osteoprogenitor cells and human AS-bone tissues. WNT16 treatment inhibited bone formation in AS-osteoprogenitor cells but not in the control. Intriguingly, AS-osteoprogenitor cells were stained markedly with ß-galactosidase for cell senescence in WNT16 treatment. Furthermore, in an H2O2 stress-induced premature senescence condition, WNT16 treatment increased cell senescence in AS-osteoprogenitor cells and WNT16 treatment under the H2O2 stress condition showed an increase in p21 protein and SASP mRNA expression. The WNT16-induced SASP expression in AS-osteoprogenitor cells was reduced in WNT16 knockdown cultures. CONCLUSION: WNT16 is highly expressed in AS and WNT16 treatment facilitated cell senescence in AS-osteoprogenitor cells during osteoblast differentiation accompanied by suppression of bone formation. The identified role of WNT16 in AS could influence bone loss in AS patients.