IL-17A has recently emerged as a potential target that regulates the extensive inflammation and abnormal bone formation observed in ankylosing spondylitis (AS). Blocking IL-17A is expected to inhibit ...bony ankylosis. Here, we investigated the effects of anti IL-17A agents in AS.
TNFα, IL-17A, and IL-12/23 p40 levels in serum and synovial fluid from patients with ankylosing spondylitis (AS), rheumatoid arthritis (RA), osteoarthritis (OA), or healthy controls (HC) were measured by ELISA. Bone tissue samples were obtained at surgery from the facet joints of ten patients with AS and ten control (Ct) patients with noninflammatory spinal disease. The functional relevance of IL-17A, biological blockades, Janus kinase 2 (JAK2), and non-receptor tyrosine kinase was assessed in vitro with primary bone-derived cells (BdCs) and serum from patients with AS.
Basal levels of IL-17A and IL-12/23 p40 in body fluids were elevated in patients with AS. JAK2 was also highly expressed in bone tissue and primary BdCs from patients with AS. Furthermore, addition of exogenous IL-17A to primary Ct-BdCs promoted the osteogenic stimulus-induced increase in ALP activity and mineralization. Intriguingly, blocking IL-17A with serum from patients with AS attenuated ALP activity and mineralization in both Ct and AS-BdCs by inhibiting JAK2 phosphorylation and downregulating osteoblast-involved genes. Moreover, JAK2 inhibitors effectively reduced JAK2-driven ALP activity and JAK2-mediated events.
Our findings indicate that IL-17A regulates osteoblast activity and differentiation via JAK2/STAT3 signaling. They shed light on AS pathogenesis and suggest new rational therapies for clinical AS ankylosis.
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.
Although risk factors of new adjacent vertebral fracture (AVF) and remote vertebral fracture (RVF) after vertebroplasty may differ, research on this topic is lacking.
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.
Retrospective cohort study.
The study subjects included 205 patients who received vertebroplasty for OVCF and were followed-up for at least 1-year.
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.
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.
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).
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.
Proximal junctional kyphosis (PJK) is a common radiographic finding after long spinal fusion. A number of studies on the causes, risk factors, prevention, and treatment of PJK have been conducted. ...However, no clear definition of PJK has been established. In this paper, we aimed to clarify the diagnosis, prevention, and treatment of PJK by reviewing relevant papers that have been published to date. A literature search was conducted on PubMed using "proximal junctional", "proximal junctional kyphosis", and "proximal junctional failure" as search keywords. Only studies that were published in English were included in this study. The incidence of PJK ranges from 5% to 46%, and it has been reported that 66% of cases occur 3 months after surgery and approximately 80% occur within 18 months. A number of studies have reported that there is no significantly different clinical outcome between PJK patients and non-PJK patients. One study showed that PJK patients expressed more pain than non-PJK patients. However, recent studies focused on proximal junctional failure (PJF), which is accepted as a severe form of PJK. PJF showed significant adverse impact in clinical aspect such as pain, neurologic deficit, ambulatory difficulties, and social isolation. Numerous previous studies have identified various risk factors and reported on the treatment and prevention of PJK. Based on these studies, we determined the clinical significance and impact of PJK. In addition, it is important to find a strategic approach to the proper treatment of PJK.
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.
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.
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.
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. β-galactosidase staining and senescence-associated secretory phenotype (SASP) using RT-qPCR were used to assess cell senescence.
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 β-galactosidase for cell senescence in WNT16 treatment. Furthermore, in an H
O
stress-induced premature senescence condition, WNT16 treatment increased cell senescence in AS-osteoprogenitor cells and WNT16 treatment under the H
O
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.
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.
Ankylosing spondylitis (AS) is characteristically male-predominant, and progressive spinal ankylosis affects male patients more severely; however, the hormonal effects in males with AS are poorly ...understood.
In the present study, the regulatory effects of dutasteride, a 5-α reductase inhibitor that blocks the conversion of testosterone to dihydrotestosterone (DHT), were examined in curdlan-administered male SKG mice to determine spinal bone formation, bone metabolism-related markers, and interleukin (IL)-17A cytokine and T cell populations. In addition, the effects of DHT on primary osteoprogenitors from the facet joints of AS patients were assessed based on osteoblast-related parameters. DHT level was measured, and the correlation with modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS) was analyzed in AS patients.
In curdlan-administered SKG mice, dutasteride treatment resulted in an increased accumulation of hydroxyapatite in the spine which was positively correlated with serum IL-17A levels. In the analysis of bone metabolism-related molecules, a decrease in sclerostin levels was observed in the sera in the dutasteride group. Continuous exposure to DHT resulted in fewer calcium deposits in AS osteoprogenitors during osteoblast differentiation. DHT-treated AS osteoprogenitors showed decreased osteocalcin and increased DKK1 and SOST1 mRNA expression, supporting the results of the in vivo experiments. Treatment with dutasteride upregulated bone formation in the spine of curdlan-administered SKG mice and DHT treatment downregulated osteoblast differentiation in vitro.
Treatment with dutasteride affected the bone formation in the spine of curdlan-treated SKG mice, and DHT treatment attenuated osteoblast differentiation in vitro. Therefore, contrary to what could be expected if osteoblasts contributed to spinal ankylosis, DHT inhibition might increase rather than decrease the progression of spinal ankylosis despite the higher levels of DHT observed in many AS patients.
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