Inositol-requiring enzyme 1 alpha (IRE1α), encoded by endoplasmic reticulum (ER) to nucleus signaling 1 (Ern1) gene, is the most conserved sensor of ER stress. IRE1α-initiated signaling pathways contribute to functional maturation of secretory cells and have been implicated in various human diseases. In this study, we examined the roles of IRE1α in odontoblast development and dentin formation in wild-type mice as well as in Dspp P19L mutant mice, which express a pathogenic variant of dentin sialophosphoprotein (P19L-DSPP) and exhibit a dentinogenesis imperfecta (DGI)-like phenotype. Western-blotting and stains-all staining analyses were used to assess whether secretion of mutant P19L-DSPP was impaired in dental pulp cells containing odontoblasts from Dspp P19L/P19L mice compared with Dspp +/+ controls. Immunohistochemistry and reverse-transcription PCR were performed to examine changes in IRE1α and its downstream target X-box binding protein 1 (XBP1) in P19L-DSPP mutant mice. To further investigate the roles of IRE1α in tooth development, we generated 2.3 Col1-Cre;Ern1 fl/fl and compound 2.3 Col1-Cre;Ern1 fl/fl ;Dspp P19L/+ mice. Structural and histological changes in mandibular molars were analyzed using plain X-ray radiography, micro-computed tomography (µCT), and histology. Additionally, in situ hybridization, quantitative real-time PCR, and immunohistochemistry were performed to compare molecular changes among these mice and Ern1 fl/fl and Ern1 fl/fl ;Dspp P19L/+ controls. Western-blotting and stains-all staining analyses support that mutant P19L-DSPP protein was not efficiently secreted into dentin matrix and was accumulated within odontoblasts. Further, immunostaining signals for phosphorylated IRE1α and total XBP1 were dramatically increased in odontoblasts and other dental pulp cells of Dspp P19L/+ and Dspp P19L/P19L mice, in comparison with Dspp +/+ mice. Consistently, there was a small increase in spliced XBP1S protein and Xbp1s mRNA levels in P19L-DSPP mutant mice. Moreover, loss of IRE1α function reduced dentin formation in 2.3 Col1-Cre;Ern1 fl/fl mice and exacerbated the dental defects of P19L-DSPP mutant mice. Notably, IRE1α deficiency did not restore the Dspp mRNA levels in the mutant mice but normalized the increased thickness of the dental pulp chamber floor dentin. These findings underscore the essential role of IRE1α in odontoblast function and dentinogenesis. Moreover, they reveal a context-dependent pathogenic role of IRE1α, providing new insights into ER stress in dental tissue development and disease.

Osteogenesis imperfecta (OI) is a rare disorder causing multiple fractures throughout life. No treatment has been shown to reduce the risk of fractures in OI. Here, we present the baseline characteristics of participants in the Treatment of Osteogenesis Imperfecta with Parathyroid Hormone and Zoledronic Acid (TOPaZ) trial. The aim of the trial is to determine whether teriparatide and zoledronic acid are superior to standard care in reducing the risk of clinical fractures. We summarised data on the baseline characteristics of TOPaZ participants, including demographics, genetic diagnosis, clinical features, bone density measurements, previous treatments, and fracture history. We recruited 350 adults with a clinical diagnosis of OI in 27 European referral centres between June 2017 and October 2022. Overall, 266 (76.2%) had type I OI, 55 (15.8%) had type IV, and 19 (5.4%) had type III. The type was unknown in 9 (2.6%). Blue sclera were noted in 80.8%, and 35.8% had dentinogenesis imperfecta. Bisphosphonates had been administered to 28.1% in the 2 years prior to enrolment. Pathogenic variants in COL1A1 or COL1A2 were found in 87.6%. Fractures occurring in the 2 years prior to enrolment were not associated with bone density. The TOPaZ population represents a unique cohort with which to study the genetic epidemiology and outcome of OI in relation to bone density and biochemical markers of bone turnover. When the trial reports, it will also provide new insights into the effect of an anabolic therapy, followed by antiresorptive treatment in the management of OI.

Osteogenesis imperfecta (OI) is a genetic disorder of mesenchymal hypoplasia and collagen defects. Whether abnormal type I collagen predisposes OI patients to multilevel lumbar disc herniation remains unclear. An 18-year-old male with childhood-diagnosed type I OI (fragility fractures, blue sclera, dentinogenesis imperfecta, severe osteoporosis) developed progressive low-back pain and bilateral radiculopathy. Magnetic resonance imaging revealed multilevel lumbar disc herniation with relatively mild nucleus pulposus degeneration. Whole-exome sequencing identified a de novo COL1A1 frameshift mutation (c.441delC, p.Gly148Aspfs*117) resulting in premature termination. AlphaFold 3 modelling predicted markedly truncated and structurally altered chains. Minimally invasive microdiscectomy, systemic antiosteoporosis therapy (bisphosphonate, calcium/vitamin D), and staged functional rehabilitation were implemented. Neurological symptoms improved postoperatively during >2 years of follow-up, while a new femoral fracture occurred in 2023. OI patients with COL1A1/COL1A2 mutations may have heightened susceptibility to disc herniation despite modest disc degeneration. Integrating magnetic resonance imaging, genetic testing, and artificial intelligence structural modelling refines diagnosis and pathophysiological understanding. Multidisciplinary management combining targeted surgery, antiosteoporosis therapy, and rehabilitation optimizes long-term outcomes.

Osteogenesis imperfecta (OI) is a congenital skeletal disorder characterized by varying degrees of bone fragility and deformities. Extraskeletal manifestations, such as blue sclera, dentinogenesis imperfecta, growth disturbance, hearing impairment, and muscle weakness, occasionally accompany OI. Many genes have been identified as causative of OI, such as the type I collagen gene and genes involved in the folding, processing, and crosslinking of type I collagen molecules, osteoblast differentiation, and bone mineralization. According to the discovery of the causative gene of OI, nosology and classifications have also been revised and the "dyadic approach" based nomenclature according to the severity and each causative gene of OI was recently adopted. Intravenous or oral bisphosphonates have been administered to treat bone fragility in children with OI and a reduction in the frequency of bone fractures has been reported. However, despite the increase of bone mineral density, evidence of bone fracture prevention is limited. Recently, excessive transforming growth factor β signaling pathway and excessive endoplasmic reticulum stress have been reported as the pathogenesis of OI, and treatment strategies based on these pathogeneses have been developed. This review summarizes the molecular basis, transition of nosology and classification, status of bisphosphonate therapy, and development of treatment strategies.

Introduction Osteogenesis imperfecta (OI) is a genetic condition most commonly caused by pathogenic variants in the genes encoding type I collagen which is the major protein of bone. Bone fractures are an important feature but it is also associated with dentinogenesis imperfecta (DI) and other dental anomalies.Aim To investigate the experiences of people living with OI related to their oral care. Method An anonymous survey developed for the Brittle Bone Society (BBS) was distributed in the United Kingdom and Ireland and was available online for three months to all members of the BBS via their website and social media platforms. Both parental reports of children with OI and adults living with OI were invited to participate.Results Of the 110 respondents, 69% identified as female (n = 76), 28% (n = 31) male, and 3% (n= 3) non-binary. The average age group was 26-45 years-old (42%; n = 46); with 21% (n = 23) below 16-years-old. In total, 45% self-reported mild OI (n = 49), 30% (n= 33) moderate, 21% (23) severe and 5% (n = 5) were unsure. Additionally, 44% (n = 48) self-reported DI, while 70% (n = 77) experienced dental problems related to OI. Concerns included appearance and bite issues. Access challenges were linked to OI severity.Conclusion Dentists need to be more aware of the effects of both DI and bisphosphonates in relation to treatment to improve care to individuals with OI, and more research is needed in this area.