Shriners Hospital for Children – Canada

Autosomal recessive hypophosphatemic rickets type 1 (ARHR1) is a rare, inherited cause of fibroblast growth factor 23 (FGF23)-mediated renal phosphate-wasting that results from homozygous inactivating pathogenic variants in the dentin matrix acidic phosphoprotein-1 (DMP1) gene. A variable clinical spectrum has been described in this condition, including features of rickets (in children), hyperostotic osteomalacia (in children and adults), bone pain, short stature, lower limb deformities, recurrent dental abscesses, and hearing defects. The purpose of this report is to describe the clinical evolution in an adult with a bi-allelic, loss of function pathogenic variant in DMP1 who developed an unusual feature of the condition—osteonecrosis of the jaw—as well as her clinical response to conventional therapy (phosphate supplementation and active vitamin D) followed by burosumab. In addition, we describe deep phenotyping in ARHR1 carriers from two unrelated kindreds who had normal clinical and serum biochemical profiles but lumbar spine bone mineral density (BMD) Z-scores that, while attenuated relative to fully affected family members, were considerably higher than a family member with two normal alleles. A trans-iliac bone biopsy from one of the ARHR1 carriers showed histomorphometric signs of a mild mineralization defect despite euphosphatemia, plus distinct osteocyte dysmorphology. These data expand the description of the clinical phenotype in fully affected individuals with ARHR1 and provide further evidence of a subclinical phenotype in the ARHR1 carrier state.

ABSTRACT Intervertebral disc (IVD) degeneration is a leading cause of chronic low back pain and a major contributor to global disability. Understanding the molecular mechanisms underlying this condition is essential for developing targeted therapies. Among these mechanisms, microRNAs (miRNAs) have emerged as critical post‐transcriptional regulators of gene expression in IVD cells, influencing key processes such as extracellular matrix (ECM) homeostasis, inflammatory signalling and cellular senescence. Extracellular vesicles (EVs), which transport miRNAs between cells, represent a promising avenue for therapeutic intervention. However, the composition of their miRNA cargo across different stages of disc degeneration remains inadequately characterised. We isolated EVs from primary human IVD cells derived from non‐degenerate, mildly degenerate, and severely degenerate tissues, and performed small RNA sequencing to profile their miRNA content. Bioinformatic analyses revealed enrichment in pathways related to ECM‐receptor interaction, focal adhesion, inflammation and cell cycle regulation. Notably, let‐7b‐5p and miR‐100‐5p were among the most abundant miRNAs and were significantly lower in EVs from degenerate discs. Functional assays demonstrated that transfection of IVD cells with let‐7b‐5p or miR‐100‐5p mimics individually suppressed IL‐1ß expression at both mRNA and protein levels, confirming their anti‐inflammatory roles. Strikingly, co‐delivery of both miRNAs enhanced suppression of pro‐inflammatory mediators, reduced senescence‐associated p16 expression and upregulated TIE2 mRNA, indicating synergistic effects in promoting a regenerative cell phenotype. These findings highlight the regulatory roles of EV‐enriched let‐7b‐5p and miR‐100‐5p in modulating inflammation and senescence in IVD cells, and underscore the potential of miRNA‐loaded EVs as cell‐free regenerative therapies for disc degeneration.

Osteogenesis imperfecta (OI) is a rare genetic disorder most often caused by mutation in genes that encode collagen type I. The collagen pathway is a complex process involving collagen folding, secretion and fibril assembly. The underlying mutation of OI causes a cascade effect resulting alterations at all levels of the collagen pathway. The objective of this study is to use knowledge synthesis to quantify the collagen-I folding kinetics, secretion kinetics, crosslinks, fibril diameter and melting temperature. A systematic search in Medline, Ovid and Web of Science, identified 1001 studies reporting on selected outcomes in OI patients. After screening, we included 51 qualitative studies, 8 quantitative and 43 studies for meta-analysis. Meta-analysis of studies with quantitative data was performed using normalized mean difference as a study-level effect size and a random-effects model with the Hunter and Smith with sample size correction. The collagen-I folding half-life dataset included 8 patients across 3 studies and had an effect size of 0.88 (confidence interval (CI) 0.31, 1.46). The collagen secretion half-life dataset included 8 patients across 7 studies and had an effect size of 0.23 (CI: −0.13, 0.59). The collagen crosslink dataset included 44 patients across 2 studies and had an effect size of 0.37 (CI: 0.09, 0.65). The fibril diameter dataset included 168 patients across 11 studies and had an effect size −0.13 (CI: −0.24, 0.02). The melting temperature dataset is expressed as absolute mean difference, it included 85 patients across 26 studies and had an effect size of −2.29 (CI: −3.32, −1.35). These findings show the collagen pathway is altered in OI, beyond the initial mutation. Our study provides new insights into collagen-I pathophysiology in OI, generating new hypotheses regarding the collagen pathway and mediating disease presentation in different tissues and overall severity.

Sensory rehabilitation in pediatric patients with traumatic spinal cord injury is challenging due to the ongoing development of their nervous systems. However, these sensory problems often result in nonuse of the impaired limb, which disturbs impaired limb rehabilitation and leads to overuse of the contralateral limb and other physical or psychological issues that may persist. Here, we introduce a soft nanomembrane sensor-enabled wearable glove system that wirelessly delivers a haptic sensation from the hand with tactile feedback responses for sensory impairment assistance. The smart glove system uses gold nanomembranes, copper-elastomer composites, and laser-induced graphene for the sensitive detection of pressure, temperature, and strain changes. The nanomaterial sensors are integrated with low-profile tactile actuators and wireless flexible electronics to offer real-time sensory feedback. The wearable system's thin-film sensors demonstrate 98% and 97% accuracy in detecting pressure and finger flexion, respectively, along with a detection coverage of real-life temperature changes as an effective rehabilitation tool. Collectively, the upper-limb sensory impairment assistance system embodies the latest in soft materials and wearable technology to incorporate soft sensors and miniaturized actuators and maximize its compatibility with human users, offering a promising solution for patient sensory rehabilitation.

The collagen triple helix is one of the structurally simplest protein motifs that still holds a lot of secrets. The GlyX-Y repeat is a business card of collagens, where Gly is required for the tight packing of three helices into a superhelix and X and Y residues are important for stabilizing the triple helix and communicating with the world. On its way to a functional molecule, collagen sequences undergo unique post-translational modifications inside and outside of the cell. Moreover, folding and secretion of collagens require specific proteins and mechanisms. Cracking the collagen triple helix codes opens up opportunities for curing associated diseases and developing new biomaterials. Here, we summarized my journey through some mysteries of the collagen triple helix and point out key unaddressed questions and problems for other researchers to pursue.