Osteogenesis Imperfecta Research Articles

A Systematic Review of the Association of Elastosis Perforans Serpiginosa and Congenital Disorders

Background: Elastosis perforans serpiginosa (EPS) is a skin condition marked by transepidermal elimination of abnormal elastic fibers, with a classical presentation of papules or plaques arranged in serpiginous, annular, or arcuate patterns on the neck, face, arms, or other flexural regions. A previous review of the literature reported that approximately 1/4 of EPS cases are associated with congenital disorders, including Down syndrome, Ehlers-Danlos syndrome, Marfan syndrome, osteogenesis imperfecta, and pseudoxanthoma elasticum. To the knowledge of these authors, no review examining the association of EPS and congenital disorders has been performed since 1968. Objective: The primary objective of this paper is to perform an updated review of the literature focused on the associations between EPS and congenital disorders. Methods: We searched electronic databases (Medline, Web of Science, PubMed) for literature pertaining to EPS and Down syndrome, Ehlers-Danlos syndrome, Marfan syndrome, osteogenesis imperfecta, and pseudoxanthoma elasticum. Results: Evidence for the association of EPS and congenital disorders is 57 cases from 48 published papers. Conclusions: Our results suggest an association between EPS and congenital disorders. However, current evidence is limited to case reports, underscoring the need for future research investigating the relationship between EPS and congenital disorders.

Orthopedic Surgery in Osteogenesis Imperfecta in Adults.

Osteogenesis imperfecta is a genetic disorder, mainly characterized by bone fragility. In adult with osteogenesis imperfecta, surgical treatment may be indicated as an emergency procedure in the event of a fracture, or as a scheduled procedure in case of patient functional impairment due to many causes, such as persistent pain, complex bone deformities, and degenerative arthropathies. In all cases, a multidisciplinary approach is recommended. It is essential to consider the patient's characteristics and expectations regarding treatment, as well as the local conditions, which may be complex due to the poor bone quality, bone deformity, and the presence of hardware implanted during childhood. The procedure can be very complex and challenging and each patient is a unique case. An accurate preoperative planning is mandatory to select the appropriate surgical technique, which can be either conservative or prosthetic, and to evaluate its feasibility and the risk-benefit ratio. The aim is to improve the patient's quality of life and autonomy as long as possible.

Adapting to Adulthood: A Review of Transition Strategies for Osteogenesis Imperfecta.

Osteogenesis Imperfecta (OI), known as "brittle bone disease," presents a rare genetic disorder characterized by bone fragility, often accompanied by skeletal deformities and extraskeletal complications. OI is primarily associated with collagen type I defects, responsible for the syndromic nature of the disease affecting a broad range of tissues. As such, its multisystemic complexity necessitates multidisciplinary care approaches in all patient life stages. OI treatment remains largely supportive, commonly including bisphosphonates and orthopedic surgeries, which show promise in children. Although rehabilitation programs for children exist, guidelines for adult care and especially the transition from pediatric to adult care, are lagging behind in OI care and research. The current systematic review summarizes the literature on OI patient pediatric to adult care transition experiences and compares OI transition approaches to other chronic diseases. The review was performed based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Systematic searches were conducted across multiple databases. Search terms encompassed synonyms and closely related phrases relevant to "OI" and "Transition to adult care". The initial screening involved the evaluation of article titles, followed by a thorough review of abstracts to assess relevance for the purpose of the current review. Programs aimed at easing the transition from pediatric to adult OI care necessitate a multifaceted approach. Collaborative efforts between different medical disciplines including pediatricians, endocrinologists, orthopedics, cardiology, pulmonology, ophthalmology, otolaryngologists, maxillofacial specialists, psychologists and medical genetics, are crucial for addressing the diverse needs of OI patients during this critical life phase. Comprehensive education, readiness assessments, personalized transition plans, and further follow-up are essential components of a structured transition framework. Further research is warranted to evaluate the feasibility and efficacy of sequential stepwise transition systems tailored to individuals with OI.

Abstract 4147633: Structural and Electrophysiological Cardiac Changes in Children with Osteogenesis Imperfecta (OI)

Introduction: Osteogenesis imperfecta (OI) is an inherited type 1 collagen disorder leading to bone fragility and increased fractures. Cardiovascular disease is the leading cause of death of adults with OI, but studies on cardiac changes from this collagen defect in children are sparse. We aim to fill this gap by assessing changes in EKG and echocardiogram (ECHO) variables in children with OI. Hypothesis: Children with OI will exhibit arrhythmogenic EKG changes and/or ECHO abnormalities which will precede changes that are documented in adults. Methods: 53 children with OI receiving care at Children’s Mercy-Kansas City were identified via ICD-10 codes. 64 with Duchenne Muscular Dystrophy (DMD, expected cardiac abnormalities) and 55 with non-accidental trauma (NAT, no expected cardiac abnormalities) served as controls. We specifically compared the most recent EKG and ECHO metrics extracted from medical charts by Kruskal-Wallis testing. Results: EKG: Children with OI differed from both NAT and DMD. OI had shorter median PR intervals (p<0.001) plus longer median QRS (p<0.001) and QTc intervals (p=0.002) than NAT. DMD had the shortest PR and longest QRS and QTc (see Table). Echo: The three groups showed no difference in systolic/diastolic BP or LV thickness. However, OI differed from NAT and/or DMD in other metrics. OI had higher end diastolic volume (p<0.001), end systolic volume (p<0.001) and stroke volume (p<0.05) than NAT, but lower values than the DMD group. Similarly, OI children had higher LV mass and LV internal diastolic and systolic diameters than NAT, but lower than DMD (p<0.001). OI LVOT diameter and Aortic root diameter were lower than NAT, but not as low as DMD (p<0.05 and p<0.001, respectively). Conclusion: Children with OI exhibit EKG and ECHO abnormalities that are similar to but less severe than for DMD, a group in which cardiovascular abnormalities are well documented. These abnormalities may be predictive of arrythmia/sudden cardiac death and/or functional decline in heart function. Our data suggest that OI children could benefit from ongoing routine cardiology studies along with orthopedic/metabolic management. Future studies would assess effects of age and OI treatments on cardiac abnormalities.

Cone Beam Computed Tomography Evaluation of Socket Healing After Third Molar Germ Extraction: A Case Series Study Including Adolescents with Osteogenesis Imperfecta Type I Treated with Bisphosphonates and Healthy Age-Matched Subjects

Bisphophonates (BPs) are widely used in Osteogenesis imperfecta (OI). Cone Beam Computed Tomography (CBCT) shows clinical usefulness in evaluating impacted teeth and adjacent structure relationships, extraction socket healing, bone mineral density (BMD) and BP-related jaw osteonecrosis (BRONJ). The aim of the study was to compare alveolar sockets and the adjacent bone area before and after third molar extraction in OI type I (OI-I) adolescents treated with BPs and age-matched healthy subjects (HSs) by CBCT. Methods: Five adolescents with genetically proven OI-I treated with BPs (three males and two females, mean age: 15.2 ± 1.78 years) and four age-matched healthy subjects (two males and two females, mean age: 15.5 ± 1.29 years) were included in this study. Eight Regions of Interest (ROIs) were evaluated: between 3.7 and 3.8 (ROI-1) and 4.7 and 4.8 (ROI-2); after 3.8 (ROI-3) and 4.8 (ROI-4); alveolar sockets 3.8 (ROI-5) and 4.8 (ROI-6); left (ROI-7) and right (ROI-8) cortical bone. Results: ROIs were evaluated on both sides of the mandible for all the subjects except one OI patient in which CBCTs were performed pre- and-post third molar extraction only on the right side. CBCT was performed 12.8 ± 4.60 and 11.5 ± 2.51 days before and 8.0 ± 1.41 and 7.7 ± 0.5 months after extraction in OI-I and HSs, respectively. BPs were discontinued 62.0 ± 36.5 months before extraction. None of the OI-I adolescents developed BRONJ. Statistically significant greater values were observed in OI-I for ROI-1 and -2 (p = 0.0464), ROI-3 and -4 (p = 0.0037) and ROI-7 and -8 (p = 0.0079) after extraction. Conclusions: This descriptive study confirms that, in OI-I adolescents treated with BPs, third molar extraction is safe, and socket healing occurs properly. In addition, it demonstrates that, if the same device and imaging conditions are used and comparisons to predetermined standard values are avoided, CBCT can be used to monitor BMD changes. The significant greater BMD observed for different ROIs in OI-I could reflect the increased secondary mineralization related to the BP-dependent reduction in bone turnover.

Height prediction of individuals with osteogenesis imperfecta by machine learning

BackgroundOsteogenesis imperfecta (OI) is a genetic disorder characterized by low bone mass, bone fragility and short stature. There is a significant gap in knowledge regarding the growth patterns across different types of OI, and the prediction of height in individuals with OI was not adequately addressed. In this study, we described the growth patterns and predicted the height of individuals with OI employing multiple machine learning (ML) models. Accurate height prediction enables effective monitoring and facilitates the development of personalized intervention plans for managing OI.MethodThis study included cross-sectional data for 323 participants with OI, and the median height Z-score for OI types I, III and IV were − 0.62 (-5.93 ~ 3.24), -3.97 (-10.44 ~ -0.02) and − 1.64 (-6.67 ~ 2.44), respectively. Based on the cross-sectional data of participants, the height curves across different gender and OI types were plotted and compared. Subsequently, feature selection techniques, specifically the filter and wrapper methods, were employed to identify predictive factors for the height of participants. Finally, multiple machine learning (ML) models were constructed for height prediction, and the performance of each model was systematically evaluated.ResultsThe analysis of height curves revealed that male with OI are significantly taller than female with OI from the age of 14 (p = 0.045), individuals with OI type III are statistically shorter than those with OI types I and IV starting from 3 years old (p = 0.006), and those with OI type IV are statistically shorter than those with OI type I from the age of 10 (p = 0.028). The application of filter and wrapper methods identified gender (p = 0.001), age (p < 0.001), Sillence types (p = 0.007), weight Z-score (p < 0.001) and aBMD Z-score (p = 0.021) as significant predictive factors for height. The optimal performance of predictive models was registered by gradient boosting classifier (GB) (bias = 5.783, accuracy = 92.59%, R2 = 0.828), random forest (RF) (bias = 6.155, accuracy = 90.12%, R2 = 0.788), ensemble machine learning (EML) (bias = 6.250, accuracy = 91.36%, R2 = 0.825) and deep neuron networks (DNNs) (bias = 6.223, accuracy = 90.12%, R2 = 0.821).ConclusionThis study analyzed a large cohort of individuals with OI and provided detailed height patterns across different gender and OI types that are crucial for assessing overall growth. Gender, age, Sillence types, weight Z-score and aBMD Z-score were identified as predictive factors for height. The predictive models of GB, RF, EML and DNNs had higher accuracy to evaluate the height of individuals with OI. This study allows guardians and physicians to timely monitor the height parameters, and facilitate the creation of personalized intervention schedules tailored to the needs of individuals with OI.

Structural Variants in COL1A1 and COL1A2 in Osteogenesis Imperfecta.

Osteogenesis Imperfecta (OI) is a heterogeneous skeletal dysplasia characterized by bone fragility, skeletal deformities, and short stature. Most commonly, it is caused by autosomal dominant variants in the type I collagen genes, COL1A1 or COL1A2. Type I collagen is the main protein of the extracellular matrix in the skeleton and changes in its structure or quantity may lead to OI. 85%-90% of OI cases occur due to sequence variants in type I collagen genes, while OI caused by structural abnormalities in type I collagen genes is less common. In most cases, haploinsufficiency of type I collagen is associated with a milder OI phenotype. Large genomic deletions often involve several genes within the same chromosomal region, leading to microdeletion syndromes with OI features. Here, we report eight Swedish patients from five unrelated families with OI due to structural variants in the COL1A1 and COL1A2 genes. One patient with OI type III had a complex rearrangement with a deletion and duplication event in COL1A2, leading to reduced COL1A2 expression. Three other patients from two different families with OI type I had whole gene deletions involving COL1A1. In one family, three affected individuals with OI type I had a small intragenic deletion of exons 11-12 in COL1A2. One patient had a 2.1 Mb de novo deletion encompassing COL1A1 and DLX3 genes and features of OI and tricho-dento-osseous syndrome. Overall, this study highlights the importance of investigating gene dosage abnormalities in patients with OI and further delineates clinical and genetic variability of OI caused by structural variants in type I collagen genes.

PRC with Double Interposition Arthroplasty for Failed Partial Wrist Arthrodesis

Abstract Background In patients with lunate fossa and proximal capitate degeneration, or failed scaphoid excision and partial wrist arthrodesis, double allograft interposition arthroplasty may allow patients to maintain wrist motion and improve pain. Description of Technique Following dorsal exposure of the carpus, a completion proximal row carpectomy is performed. Suture anchors are placed evenly along the perimeter of the distal radius and used to secure a precut sheet of allograft. Additional suture anchors are placed at the proximal aspect of the distal carpal row, securing a second piece of allograft to the proximal capitate and hamate. Patients, Methods, and Results We present the case of a female with osteogenesis imperfecta who failed prior partial wrist fusion for treatment of scapholunate advanced collapse. She declined wrist arthrodesis and was not a candidate for total wrist arthroplasty. Proximal row carpectomy with double interposition arthroplasty provided resolution of her pain and preserved her wrist range of motion. Conclusions Double interposition arthroplasty may provide reliable pain relief and wrist range of motion for patients with advanced wrist arthritis in whom traditional salvage procedures are contraindicated or have failed. Use of this technique offers benefits that may minimize complications and improve longevity compared with previously described allograft interposition techniques.

Rigid intramedullary nailing of lower limb segments in children and adolescents with metabolic bone disease.

Children and adolescents with metabolic bone disease present to the orthopedic surgeon with pain, fractures (which may be impending), and deformity. Different modalities of orthopedic management are available. Scant literature exists on the use of rigid intramedullary nailing in this population. This study sought to evaluate the utilization of this treatment modality in the pediatric cohort, focusing on indications, techniques, and outcomes of the procedures. A retrospective review was performed over an 11-year period at a single tertiary pediatric institution in the UK. Medical records and radiographs were reviewed. Preoperative surgical and medical management, time to bony union, and complications were specifically ascertained. Twenty-seven patients (63 lower limb segments) had rigid intramedullary nailing over the specified period. The majority of patients had an underlying diagnosis of osteogenesis imperfecta or fibrous dysplasia (including McCune Albright Syndrome). Surgical indications included acute fractures, prophylactic stabilization, previous nonunion and malunions, deformity correction, and limb lengthening. All fractures healed and deformity correction was successful. In one patient, delayed union occurred after deformity correction and was successfully treated with dynamization. Fractures healed faster than corrective osteotomies. Complications included implant prominence, cortical penetrance, and screw loosening. Nonunion occurred with limb lengthening in one patient. Rigid intramedullary nailing is a safe and effective method of treatment for lower limb fractures and deformities in children and adolescents. This technique is, therefore, recommended for patients with metabolic bone disease. However, care must be taken in preoperative surgical planning and a multidisciplinary approach should be utilized.

Regulated N-glycosylation controls chaperone function and receptor trafficking.

One-fifth of human proteins are N-glycosylated in the endoplasmic reticulum (ER) by two oligosaccharyltransferases, OST-A and OST-B. Contrary to the prevailing view of N-glycosylation as a housekeeping function, we identified an ER pathway that modulates the activity of OST-A. Genetic analyses linked OST-A to HSP90B1, an ER chaperone for membrane receptors, and CCDC134, an ER luminal protein. During its translocation into the ER, an N-terminal peptide in HSP90B1 templates the assembly of a translocon complex containing CCDC134 and OST-A that protects HSP90B1 during folding, preventing its hyperglycosylation and degradation. Disruption of this pathway impairs WNT and IGF1R signaling and causes the bone developmental disorder osteogenesis imperfecta. Thus, N-glycosylation can be regulated by specificity factors in the ER to control cell surface receptor signaling and tissue development.

Zoledronate Therapy in Osteogenesis Imperfecta: Perspectives in Indonesia Tertiary Hospital.

Osteogenesis imperfecta (OI) is a rare disease with an estimated incidence of between 1/25,000 and 1/10,000 globally. The main treatment for OI is the administration of bisphosphonate drugs. Research on clinical, radiographic, and biochemical markers to monitor patients with OI treated with zoledronate can be challenging in countries in which patients have limited national health insurance. We aimed to examine patients with OI treated in Indonesia with a minimum follow-up period of 2 years. An observational study was conducted of all patients with OI treated with zoledronate between 2021 and 2023 at a tertiary hospital in Indonesia. We evaluated the paediatric quality of life (PedsQL), bone mineral density (BMD), and alkaline phosphatase (ALP) level before and after zoledronate treatment. To monitor safety, serum creatinine and calcium levels were also measured. Eleven boys (55%) and nine girls (45%), with an average age of 6.9 years (range, 4-17 years), were included. After 2 years of zoledronate treatment, the total PedsQL score increased from 66.7 to 76.9 (P=0.0001) and the mean lumbar and total body BMD increased from 0.467 and 0.501 to 0.599 g/cm2, and 0.626 g/cm2 (P=0.001), respectively. The ALP level decreased from 310.6 to 186.4 mg/mL (P=0.0001). Neither serum creatinine (P=0.586) nor calcium (P=0.53) levels changed from the pre-treatment to 2 years post-treatment time points. Zoledronate was safe and effective for the treatment of OI. There were significant improvements in the quality of life and BMD in patients with OI. The ALP level decreased, but serum creatinine and calcium levels were not affected by zoledronate.

Dentinogenesis imperfecta in a 6-year-old male neutered Labrador retriever: Case report with atypical clinical presentation and treatment review

This case report details the diagnosis and treatment of dentinogenesis imperfecta in a 6-year-old neutered male Labrador, presenting without concurrent osteogenesis imperfecta. Diagnostic modalities, including radiographs, CT imaging, and histopathological examination, are reviewed in conjunction with the latest literature on canine dentinogenesis imperfecta. This patient presented at a more advanced age than typically reported cases. The clinical history, as provided by referring veterinarians, documented fractured deciduous teeth with delayed exfoliation. By 10 months of age, the patient’s permanent dentition exhibited a translucent appearance and structural anomalies. Upon presentation to Eastcott Referrals the patient was experiencing significant oral pain and exhibited generalised coronal wear with yellow/brown intrinsic discolouration. CT imaging revealed that all teeth had endodontic disease and associated apical periodontitis, with varied root canal widths indicating that teeth succumbed to endodontic disease at different time points. The treatment protocol involved staged full-mouth extractions, resulting in the complete resolution of clinical symptoms. This case underscores the importance of early diagnosis and intervention in managing dentinogenesis imperfecta in dogs.

Osteoclast indices in osteogenesis imperfecta: systematic review and meta-analysis.

Osteogenesis imperfecta (OI) is a rare bone fragility disorder caused by mutations in genes encoding collagen type I or that affect its processing. Alterations in osteoclasts were suggested to contribute to OI pathophysiology. We aimed to systematically identify studies reporting measures of osteoclast formation and function in patients and mouse models of OI, to quantify OI-induced changes. The systematic search of Medline, Ovid, and Web of Science identified 798 unique studies. After screening, we included 23 studies for meta-analysis, reporting osteoclast parameters in 310 patients with OI of 9 different types and 16 studies reporting osteoclast parameters in 406 animals of 11 different OI mouse models. The standardized mean difference with 95% confidence interval (CI) was used as the effect size, and random-effects meta-analysis was performed. In patients with OI, collagen degradation markers were significantly higher compared with age-matched controls, with an effect size of 1.23 (CI: 0.36, 2.10]. Collagen degradation markers were the most elevated in the 3- to 7-year-old age group and in patients with more severe forms of OI. Bone histomorphometry demonstrated the trends for higher osteoclast numbers (1.16; CI: -0.22, 2.55) and osteoclast surface (0.43; CI: -0.63, 1.49), and significantly higher eroded surface (3.24; CI: 0.51, 5.96) compared with age-matched controls. In OI mice, meta-analysis demonstrated significant increases in collagen degradation markers (1.59; CI: 1.07, 2.11), in osteoclast numbers (0.94; CI: 0.50, 1.39), osteoclast surface (0.73; CI: 0.22, 1.23), and eroded surface (1.31; CI: 0.54, 2.08). The largest differences were in OI mice with the mutations in Col1a1 and Col1a2 genes. There were no differences between males and females in clinical or animal studies. Quantitative estimates of changes in osteoclast indices and their variance for patients with OI are important for planning future studies. We confirmed that similar changes are observed in mice with OI, supporting their translational utility.

Annual hearing screening in children with Osteogenesis Imperfecta: results from the first five years in Glasgow

BackgroundHearing loss is common in people with osteogenesis imperfecta (OI), although exactly how common is unknown. The prevalence of hearing loss in children with OI has been reported to be anything from 0 to 77%. Brittle Bone Society guidelines suggest that, unless there are ear symptoms, children with OI should have their hearing tested every three years starting at age three. There is limited evidence to support this recommendation. We postulate that annual hearing screening would be easier to manage and would have a worthwhile pick-up rate. MethodsIn March 2019 we began a programme of annual hearing screening for all children (ages 0-16) with OI. We collected data on age, genotype, otoscopy findings, tympanometry findings, audiometric test results and subsequent outcomes for the first five years of our programme (2019 – 2024). ResultsNineteen children with OI participated in the screening programme. Only one abnormality was found: a unilateral mild hearing impairment with a type B tympanogram, suggesting middle ear effusion. This was present in year 2 of the programme but resolved by year 3. ConclusionThe screening programme has a low pickup rate (5%) for new otological problems in the paediatric population. However, we believe that the low cost and small workload associated with the screening programme justifies continuing it until further conclusions can be drawn.

Jazz Musicians and Their Disabilities: Django Reinhardt, Les Paul, and Michel Petrucciani.

Musicians with physical disabilities who achieved stardom are part of the lore of popular music. Guitarist Django Reinhardt contrived alternate fingering patterns necessitated by burn contractures of his left hand. Les Paul, a legend in the development of the solid body electric guitar and multitrack recording, mangled his right arm in a car wreck so severely that his elbow was set permanently at 90° so he could continue to play guitar. Michel Petrucciani suffered from osteogenesis imperfecta, a condition that stunted his growth to the point where he used a special attachment to reach the sustaining pedals of his piano. Their stories show the force of human genius in music.

Postpartum multiple vertebral fractures in a patient with osteogenesis imperfecta type I: A case report and literature review

Postpartum multiple vertebral fractures in a patient with osteogenesis imperfecta type I: A case report and literature review

Outcome of Locking Plate Fixation Adjunctive to Intramedullary Rodding in Osteogenesis Imperfecta Patients.

An intramedullary rodding is the preferred fixation method in limb stabilization of OI patients. However, the intramedullary rod may not provide adequate fixation and rotational stability, especially in adolescents and adults. The incorporation of adjunctive plate fixation alongside intramedullary rodding has been introduced to enhance this stability, although its complications remain insufficiently understood. The goal of this study was to explore the outcomes of adjunctive plating in conjunction with intramedullary rodding for limb stabilization in OI patients, emphasizing the complications related to the plates during the healing phase and following plate removal. This retrospective study examined 74 limb segments from 45 patients with OI who underwent intramedullary rodding and adjunctive plating from 2008 to 2022. Criteria for inclusion comprised surgical treatment followed by a minimum of 2 years of follow-up or complication before that time point. The need for adjunctive plating arose from inadequate fixation, rotational instability, and persistent cortical gaps with intramedullary rodding alone. Medical records and follow-up radiographs were reviewed to assess the healing of the target lesion and any complications. The study encompassed 30 males and 15 females, ranging in age from 4 to 38 years, with 51 femoral and 23 tibial segments receiving treatment. Union was successfully achieved in 63 cases (85.3%), with an average union time of 14.4 months. Plates were subsequently removed in 62 cases after an average duration of 18.0 months. Before union, 11 revision surgeries were performed in 4 peri-implant fractures, 1 screw pull-out, and 6 failure of union. One sustained peri-implant fracture after the union. Following the removal of plates, complications included 10 refractures at screw sites, 3 progressive angulations at the previously targeted lesions, and 1 osteomyelitis. Kaplan-Meier analysis revealed that half of the refractures occurred within 1.8 years postplate removal. The overall complication showed borderline significance (P=0.056) among age groups. All the plate-related complications occurred at the diaphyseal, unicortical screws. Plate fixation, when used as an adjunct to intramedullary rodding, effectively stabilizes limbs in OI patients when intramedullary rods alone are inadequate. Nevertheless, given the significant risks associated with plate-related complications, adjunctive plating should be employed selectively only in instances where the union is unlikely to be achieved with intramedullary rodding alone. Level IV-case series.

Modulation of biomineralization morphology by phosphorylated collagen peptides: insights into osteogenesis imperfecta pathophysiology.

Osteogenesis imperfecta (OI) is a hereditary skeletal disorder characterized by bone fragility and deformities, primarily attributed to defects in type I collagen, the most abundant structural protein in humans. Multiple phosphorylation sites have been detected within collagen, suggesting that phosphorylation may influence mineralization processes, thereby impacting the development of OI. In this study, we investigated the modulation of biomineralization morphology by phosphorylated collagen peptides mimicking Gly-Ser mutations in osteogenesis imperfecta. A series of collagen peptide sequences, including GPO13S, GPO13pS, GPO12S, GPO12pS, GPO11S, and GPO11pS, were synthesized to explore the role of phosphorylation in peptide stability and its templating effect on biomineralization. The CD results indicated that the phosphorylation of Gly-pSer mutants reduces the stability of collagen peptides. SEM images revealed that phosphorylated peptides acted as templates, guiding the morphology of calcium carbonate into either olive-like or spherical structures, depending on their conformational state of the peptides. Non-phosphorylated peptides maintained a calcite crystal structure. The XRD patterns predominantly exhibited peaks associated with calcite and vaterite for GPO13pS-CaCO3, GPO12pS-CaCO3, and GPO11pS-CaCO3, and peaks associated with calcite for GPO13S-CaCO3, GPO12S-CaCO3, and GPO11S-CaCO3, indicating a transformation of mesocrystals influenced by peptide phosphorylation. Our findings elucidate the crucial role of phosphorylated collagen peptides in mediating biomineralization morphology and polymorph selection, offering insights into the complex pathophysiology of OI.

Developing Stapled Aptamers with a Constrained Conformation for Osteogenesis Imperfect Therapeutics.

Despite the extensive development of aptamers in basic research, only a limited number have successfully progressed to clinical trials. This limitation is primarily attributed to the inherent instability of aptamers' conformation, resulting in low affinity, poor serum stability, and inconsistent potency, posing a significant challenge to their stabilization. Herein, we established a feasible strategy to develop staple aptamers using the predicted binding conformations and titration cross-linking (TTC) method. Through this strategy, we successfully synthesized various stapled sclerostin aptamers with over 70% yield. Importantly, we demonstrated that stapled aptamers significantly enhanced their affinity (approximately 20-fold) and serum stability (negligible degradation within 32 h). Moreover, in an osteogenesis imperfecta mouse model (Col1a2+/G610C mice), the stapled aptamer (named c-0127OA) exhibited a potent antagonistic effect on sclerostin, leading to enhanced anabolic bone anabolic potential. Collectively, our established stapling strategy is effective in stabilizing aptamers' conformation, with c-0127OA emerging as a promising therapeutic candidate for osteogenesis imperfecta.

Evaluating Biomarkers of Bone Health After an 8-Week Walking Program in Non-Ambulatory Stroke Survivors: A Pilot Study.

Background/Objectives: Stroke survivors have a significantly increased likelihood of developing osteoporosis, a condition characterized by weak and brittle bones as well as an elevated risk of bone fractures. However, previous studies on exercise intervention have mostly been on stroke survivors who are able to walk. The objective of this study was to examine the effect of walking exercise on bone health in non-ambulatory stroke survivors. Methods: This pre- and post-test study enrolled a group of chronic non-ambulatory stroke survivors. They were instructed to complete an 8-week aerobic walking exercise program, three sessions per week. Serum concentrations of osteocalcin (OC) and carboxy-terminal telopeptides of type I collagen (ICTP) were evaluated at baseline and after completing the walking exercise program. In addition, we assessed the ambulation capacity and balance control using the functional ambulation category (FAC) and Berg Balance Scale (BBS), respectively. Results: A total of 9 out of 10 non-ambulatory stroke survivors who were recruited completed the intervention. The serum concentration of OC significantly increased from 8.51 ± 2.28 ng/mL to 9.39 ± 2.97 ng/mL (p < 0.10). The serum concentration of ICTP significantly increased from 4.45 ± 2.58 ng/mL to 5.31 ± 2.92 ng/mL (p < 0.10). Both FAC and BBS scores significantly improved from 1.0 ± 0 to 1.33 ± 0.5 (p < 0.1) and from 7.22 ± 10.02 to 15.78 ± 14.81 (p < 0.01), respectively. Conclusions: The findings of this pilot study suggest that walking exercise may improve bone health by initiating a bone remodeling process in chronic non-ambulatory stroke survivors.