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ELife Jul 2023Ossification of the posterior longitudinal ligament of the spine (OPLL) is an intractable disease leading to severe neurological deficits. Its etiology and pathogenesis... (Meta-Analysis)
Meta-Analysis
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.
Topics: Animals; Mice; Osteogenesis; Genome-Wide Association Study; Diabetes Mellitus, Type 2; Spine; Ossification of Posterior Longitudinal Ligament
PubMed: 37461309
DOI: 10.7554/eLife.86514 -
Nature Sep 2023Craniosynostosis is a group of disorders of premature calvarial suture fusion. The identity of the calvarial stem cells (CSCs) that produce fusion-driving osteoblasts in...
Craniosynostosis is a group of disorders of premature calvarial suture fusion. The identity of the calvarial stem cells (CSCs) that produce fusion-driving osteoblasts in craniosynostosis remains poorly understood. Here we show that both physiologic calvarial mineralization and pathologic calvarial fusion in craniosynostosis reflect the interaction of two separate stem cell lineages; a previously identified cathepsin K (CTSK) lineage CSC (CTSK CSC) and a separate discoidin domain-containing receptor 2 (DDR2) lineage stem cell (DDR2 CSC) that we identified in this study. Deletion of Twist1, a gene associated with craniosynostosis in humans, solely in CTSK CSCs is sufficient to drive craniosynostosis in mice, but the sites that are destined to fuse exhibit an unexpected depletion of CTSK CSCs and a corresponding expansion of DDR2 CSCs, with DDR2 CSC expansion being a direct maladaptive response to CTSK CSC depletion. DDR2 CSCs display full stemness features, and our results establish the presence of two distinct stem cell lineages in the sutures, with both populations contributing to physiologic calvarial mineralization. DDR2 CSCs mediate a distinct form of endochondral ossification without the typical haematopoietic marrow formation. Implantation of DDR2 CSCs into suture sites is sufficient to induce fusion, and this phenotype was prevented by co-transplantation of CTSK CSCs. Finally, the human counterparts of DDR2 CSCs and CTSK CSCs display conserved functional properties in xenograft assays. The interaction between these two stem cell populations provides a new biologic interface for the modulation of calvarial mineralization and suture patency.
Topics: Humans; Mice; Animals; Craniosynostoses; Osteogenesis; Cell Lineage; Phenotype; Stem Cells
PubMed: 37730988
DOI: 10.1038/s41586-023-06526-2 -
Advanced Science (Weinheim,... Jul 2023Heterotopic ossification (HO) represents an unwanted ossific wound healing response to the soft tissue injury which caused catastrophic limb dysfunction. Recent studies...
Heterotopic ossification (HO) represents an unwanted ossific wound healing response to the soft tissue injury which caused catastrophic limb dysfunction. Recent studies established the involvement of inflammation and cellular senescence in the tissue healing process, though their role in HO still remained to be clarified. Here, a novel crosstalk where the pyroptotic macrophages aroused tendon-derived stem cells (TDSCs) senescence is revealed to encourage osteogenic healing during trauma-induced HO formation. Macrophage pyroptosis blockade reduces the senescent cell burden and HO formation in NLRP3 knockout mice. Pyroptosis-driven IL-1β and extracellular vesicles (EVs) secretion from macrophages are determined to motivate TDSCs senescence and resultant osteogenesis. Mechanistically, pyroptosis in macrophages enhances the exosomal release of high mobility group protein 1 (HMGB1), which directly bounds TLR9 in TDSCs to trigger morbid signaling. NF-κB signaling is confirmed to be the converging downstream pathway of TDSCs in response to HMGB1-containing EVs and IL-1β. This study adds insights into aberrant regeneration-based theory for HO formation and boosts therapeutic strategy development.
Topics: Animals; Mice; Cellular Senescence; HMGB1 Protein; Macrophages; NLR Family, Pyrin Domain-Containing 3 Protein; Ossification, Heterotopic; Wound Healing
PubMed: 37204068
DOI: 10.1002/advs.202207383 -
Clinical Case Reports Nov 2023Fibrodysplasia ossificans progressiva is a progressively debilitating condition associated with significant morbidity caused by heterotopic ossification. Recognition of...
KEY CLINICAL MESSAGE
Fibrodysplasia ossificans progressiva is a progressively debilitating condition associated with significant morbidity caused by heterotopic ossification. Recognition of the early signs of hallux valgus and painful soft tissue nodules can assist in the early diagnosis of this condition. Periodic radiographic examination is mandatory to monitor the disease progression.
ABSTRACT
Fibrodysplasia ossificans progressiva is a rare condition with an estimated prevalence of one in two million individuals. The condition is characterized by widespread heterotrophic ossification of skeletal muscles and ligaments. We report the case of an 8-year-old female patient and show the radiological progression of the condition.
PubMed: 37942184
DOI: 10.1002/ccr3.8165 -
Biomolecules Apr 2024The formation of bone outside the normal skeleton, or heterotopic ossification (HO), occurs through genetic and acquired mechanisms. Fibrodysplasia ossificans... (Review)
Review
The formation of bone outside the normal skeleton, or heterotopic ossification (HO), occurs through genetic and acquired mechanisms. Fibrodysplasia ossificans progressiva (FOP), the most devastating genetic condition of HO, is due to mutations in the gene and is relentlessly progressive. Acquired HO is mostly precipitated by injury or orthopedic surgical procedures but can also be associated with certain conditions related to aging. Cellular senescence is a hallmark of aging and thought to be a tumor-suppressive mechanism with characteristic features such as irreversible growth arrest, apoptosis resistance, and an inflammatory senescence-associated secretory phenotype (SASP). Here, we review possible roles for cellular senescence in HO and how targeting senescent cells may provide new therapeutic approaches to both FOP and acquired forms of HO.
Topics: Humans; Ossification, Heterotopic; Cellular Senescence; Myositis Ossificans; Animals; Activin Receptors, Type I
PubMed: 38672501
DOI: 10.3390/biom14040485 -
Current Osteoporosis Reports Oct 2023The study aims to provide updated information on the genetic factors associated with the diagnoses 'Diffuse Idiopathic Skeletal Hyperostosis' (DISH), 'Ossification of... (Review)
Review
PURPOSE OF REVIEW
The study aims to provide updated information on the genetic factors associated with the diagnoses 'Diffuse Idiopathic Skeletal Hyperostosis' (DISH), 'Ossification of the Posterior Longitudinal Ligament' (OPLL), and in patients with spinal ligament ossification.
RECENT FINDINGS
Recent studies have advanced our knowledge of genetic factors associated with DISH, OPLL, and other spinal ossification (ossification of the anterior longitudinal ligament [OALL] and the yellow ligament [OYL]). Several case studies of individuals afflicted with monogenic disorders, such as X-linked hypophosphatemia (XLH), demonstrate the strong association of fibroblast growth factor 23-related hypophosphatemia with OPLL, suggesting that pathogenic variants in PHEX, ENPP1, and DMP1 are associated with FGF23-phosphate wasting phenotype and strong genetic factors placing patients at risk for OPLL. Moreover, emerging evidence demonstrates that heterozygous and compound heterozygous ENPP1 pathogenic variants inducing 'Autosomal Recessive Hypophosphatemic Rickets Type 2' (ARHR2) also place patients at risk for DISH and OPLL, possibly due to the loss of inhibitory plasma pyrophosphate (PP) which suppresses ectopic calcification and enthesis mineralization. Our findings emphasize the importance of genetic and plasma biomarker screening in the clinical evaluation of DISH and OPLL patients, with plasma PP constituting an important new biomarker for the identification of DISH and OPLL patients whose disease course may be responsive to ENPP1 enzyme therapy, now in clinical trials for rare calcification disorders.
Topics: Humans; Hyperostosis, Diffuse Idiopathic Skeletal; Osteogenesis; Ossification of Posterior Longitudinal Ligament; Biomarkers; Ligaments
PubMed: 37530996
DOI: 10.1007/s11914-023-00814-6