Ectopic endochondral ossification in the tendon/ligament is caused by repetitive mechanical overload or inflammation. Tendon stem/progenitor cells (TSPCs) contribute to tissue repair, and some express lubricin [proteoglycan 4 (PRG4)]. However, the mechanisms of ectopic ossification and association of TSPCs are not yet known. Here, we investigated the characteristics of Prg4-positive ( ⁺ ) cells and identified that R-spondin 2 (RSPO2), a WNT activator, is specifically expressed in a distinct Prg4 ⁺ TSPC cluster. The Rspo2 ⁺ cluster was characterized as mostly undifferentiated, and RSPO2 overexpression suppressed ectopic ossification in a mouse Achilles tendon puncture model via chondrogenic differentiation suppression. RSPO2 expression levels in patients with ossification of the posterior longitudinal ligament were lower than those in spondylosis patients, and RSPO2 protein suppressed chondrogenic differentiation of human ligament cells. RSPO2 was induced by inflammatory stimulation and mechanical loading via nuclear factor κB. Rspo2 ⁺ cells may contribute to tendon/ligament homeostasis under pathogenic conditions.

Ossification of the posterior longitudinal ligament of the spine (OPLL) is an intractable disease leading to severe neurological deficits. Its etiology and pathogenesis are primarily unknown. The relationship between OPLL and comorbidities, especially type 2 diabetes (T2D) and high body mass index (BMI), has been the focus of attention; however, no trait has been proven to have a causal relationship. We conducted a meta-analysis of genome-wide association studies (GWASs) using 22,016 Japanese individuals and identified 14 significant loci, 8 of which were previously unreported. We then conducted a gene-based association analysis and a transcriptome-wide Mendelian randomization approach and identified three candidate genes for each. Partitioning heritability enrichment analyses observed significant enrichment of the polygenic signals in the active enhancers of the connective/bone cell group, especially H3K27ac in chondrogenic differentiation cells, as well as the immune/hematopoietic cell group. Single-cell RNA sequencing of Achilles tendon cells from a mouse Achilles tendon ossification model confirmed the expression of genes in GWAS and post-GWAS analyses in mesenchymal and immune cells. Genetic correlations with 96 complex traits showed positive correlations with T2D and BMI and a negative correlation with cerebral aneurysm. Mendelian randomization analysis demonstrated a significant causal effect of increased BMI and high bone mineral density on OPLL. We evaluated the clinical images in detail and classified OPLL into cervical, thoracic, and the other types. GWAS subanalyses identified subtype-specific signals. A polygenic risk score for BMI demonstrated that the effect of BMI was particularly strong in thoracic OPLL. Our study provides genetic insight into the etiology and pathogenesis of OPLL and is expected to serve as a basis for future treatment development.

Context: Conventional treatment of X-linked hypophosphatemia (XLH) was reported to prevent dental complications, but whether the preventive effect was different among different types of teeth, including anterior teeth and molar teeth, is uncertain. Evidence of the preventive effect of conventional treatment on ectopic ossifications is also limited. Objective: To compare dental complications and ectopic ossifications among adults with XLH with early (<5 years old) or late (≥5 years old) conventional treatment. Methods: This retrospective observational study included a total of 30 adults with XLH; orthopantomograms, spinal computed tomography scans, and X-rays of hip/knee joints were studied. Dental complications, including the decayed, missing, filled (DMF) index and devitalized teeth, apical periodontitis, and periodontitis, were evaluated. The ossification of the anterior/posterior longitudinal ligament and yellow ligament indexes (OA/OP/OY indexes) and the sum of the OA/OP/OY indexes (OS index) were utilized to evaluate the severity of spinal ligament ossification. The severity of the hip/knee osteophytes was evaluated using the Kellgren–Lawrence (KL) classification. Results: The number of sound teeth was significantly lower and the DMF index was significantly higher in patients with late treatment. The severity of dental complications in the anterior tooth and molar tooth, OA/OP/OY/OS index, and KL grade were not significantly different among patients with early treatment and those with late treatment. Conclusion: Early treatment could prevent dental complications but did not prevent ectopic ossification in adult patients with XLH. The difference in the preventive effect was not observed among different types of teeth.

Several previous reports have elucidated the mortality and incidence of complications after pediatric scoliosis surgery using nationwide databases. However, all of these studies were conducted in North America. Hence, this study aimed to identify the incidence and risk factors for in-hospital mortality and morbidity in pediatric scoliosis surgery, utilizing the Diagnosis Procedure Combination database, a national inpatient database in Japan.We retrospectively extracted data for patients aged less than 19 years who were admitted between 01 June 2010 and 31 March 2013 and underwent scoliosis surgery with fusion. The primary outcomes were in-hospital death and postoperative complications, including surgical site infection, ischemic heart disease, acute renal failure, pneumonia, stroke, disseminated intravascular coagulation, pulmonary embolism, and urinary tract infection.We identified 1,703 eligible patients (346 males and 1,357 females) with a mean age of 14.1 years. There were no deaths among the patients. At least one postoperative complication was found in 49 patients (2.9%). The most common complication was surgical site infection (1.4%). The multivariable logistic regression analysis showed that male sex (odds ratio, 2.22; 95% confidence interval, 1.28-3.70), comorbid diabetes (7.00; 1.56-31.51), and use of allogeneic blood transfusion (3.43; 1.86-6.41) were associated with the occurrence of postoperative complications. The present nationwide study elucidated the incidence and risk factors for in-hospital mortality and morbidity following surgery for pediatric scoliosis in an area other than North America. Diabetes was identified for the first time as a risk factor for postoperative complications in pediatric scoliosis surgery.