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Nature Communications Jun 2024Acoustic vibrations of matter convey fundamental viscoelastic information that can be optically retrieved by hyperfine spectral analysis of the inelastic Brillouin...
Acoustic vibrations of matter convey fundamental viscoelastic information that can be optically retrieved by hyperfine spectral analysis of the inelastic Brillouin scattered light. Increasing evidence of the central role of the viscoelastic properties in biological processes has stimulated the rise of non-contact Brillouin microscopy, yet this method faces challenges in turbid samples due to overwhelming elastic background light. Here, we introduce a common-path Birefringence-Induced Phase Delay (BIPD) filter to disentangle the polarization states of the Brillouin and Rayleigh signals, enabling the rejection of the background light using a polarizer. We demonstrate a 65 dB extinction ratio in a single optical pass collecting Brillouin spectra in extremely scattering environments and across highly reflective interfaces. We further employ the BIPD filter to image bone tissues from a mouse model of osteopetrosis, highlighting altered biomechanical properties compared to the healthy control. Results herald new opportunities in mechanobiology where turbid biological samples remain poorly characterized.
Topics: Animals; Birefringence; Mice; Viscosity; Elasticity; Biomechanical Phenomena; Bone and Bones; Light; Scattering, Radiation
PubMed: 38898004
DOI: 10.1038/s41467-024-49419-2 -
Bone Research Jun 2024DNAX-associated protein 12 kD size (DAP12) is a dominant immunoreceptor tyrosine-based activation motif (ITAM)-signaling adaptor that activates costimulatory signals...
DNAX-associated protein 12 kD size (DAP12) is a dominant immunoreceptor tyrosine-based activation motif (ITAM)-signaling adaptor that activates costimulatory signals essential for osteoclastogenesis. Although several DAP12-associated receptors (DARs) have been identified in osteoclasts, including triggering receptor expressed on myeloid cells 2 (TREM-2), C-type lectin member 5 A (CLEC5A), and sialic acid-binding Ig-like lectin (Siglec)-15, their precise role in the development of osteoclasts and bone remodeling remain poorly understood. In this study, mice deficient in Trem-2, Clec5a, Siglec-15 were generated. In addition, mice double deficient in these DAR genes and FcεRI gamma chain (FcR)γ, an alternative ITAM adaptor to DAP12, were generated. Bone mass analysis was conducted on all mice. Notably, Siglec-15 deficient mice and Siglec-15/FcRγ double deficient mice exhibited mild and severe osteopetrosis respectively. In contrast, other DAR deficient mice showed normal bone phenotype. Likewise, osteoclasts from Siglec-15 deficient mice failed to form an actin ring, suggesting that Siglec-15 promotes bone resorption principally by modulating the cytoskeletal organization of osteoclasts. Furthermore, biochemical analysis revealed that Sigelc-15 activates macrophage colony-stimulating factor (M-CSF)-induced Ras-associated protein-1 (RAP1)/Ras-related C3 botulinum toxin substrate 1 (Rac1) pathway through formation of a complex with p130CAS and CrkII, leading to cytoskeletal remodeling of osteoclasts. Our data provide genetic and biochemical evidence that Siglec-15 facilitates M-CSF-induced cytoskeletal remodeling of the osteoclasts.
Topics: Animals; Osteoclasts; Signal Transduction; Macrophage Colony-Stimulating Factor; rap1 GTP-Binding Proteins; Mice; Cytoskeleton; Mice, Knockout; Mice, Inbred C57BL; Membrane Proteins; rac GTP-Binding Proteins; Membrane Glycoproteins; Receptors, Immunologic; Immunoglobulins
PubMed: 38849345
DOI: 10.1038/s41413-024-00340-w -
Radiologie (Heidelberg, Germany) Jun 2024We were looking for an osteoporosis screening in computed tomography (CT) exams, simple and without additional examinations. We hypothesized that the criterion of...
BACKGROUND
We were looking for an osteoporosis screening in computed tomography (CT) exams, simple and without additional examinations. We hypothesized that the criterion of "decreasing cortical thickness", may have an influence on the hard palate. Therefore, we investigated whether thickness of the hard palate (HPT) may serve as an indicator of osteoporosis for patients imaged for other reasons.
METHODS
Patients with dual-energy x-ray absorptiometry (DXA) and CT were identified by a radiology information system (RIS)-based, full-text search. Measurement of thickness of hard palate done in existing CT image by radiologist and dentist and compared with available findings and DXA measurements.
RESULTS
We identified a "test group": 57 patients with DXA and CT available out of 449 patient population and we selected further 70 patients without bone diseases as "control groups". The measurements showed that HPT correlated with age and bone density. The mean HPT was 2.4 mm in normal, 0.9 mm in osteopenia, 0.8 mm in osteoporosis and 5.3 mm in osteopetrosis case. No bone "healthy" patient fell below 1 mm. The relationship between bone density and HPT has not been described previously. HPT was highest in the bone-healthy group and decreased with age, osteopenia, and osteoporosis. Osteopetrosis, as a disease with increased bone density showed an increase in HPT.
CONCLUSIONS
HPT correlates with bone disease. We propose a new criterion for assessment on CT and digital volume tomography (DVT) or cone beam computed tomography (CBCT). A threshold of 1.0 mm when applying a simple measurement of HPT on Head CT or DVT may serve as an indicator for potential osteopenia or osteoporosis as incidental finding without extra imaging further diagnosis and treatment leading to early notice of Osteoporosis.
PubMed: 38842551
DOI: 10.1007/s00117-024-01318-9 -
The Journal of Biological Chemistry Jun 2024Together with its β-subunit OSTM1, ClC-7 performs 2Cl/H exchange across lysosomal membranes. Pathogenic variants in either gene cause lysosome-related pathologies,...
Together with its β-subunit OSTM1, ClC-7 performs 2Cl/H exchange across lysosomal membranes. Pathogenic variants in either gene cause lysosome-related pathologies, including osteopetrosis and lysosomal storage. CLCN7 variants can cause recessive or dominant disease. Different variants entail different sets of symptoms. Loss of ClC-7 causes osteopetrosis and mostly neuronal lysosomal storage. A recently reported de novo CLCN7 mutation (p.Tyr715Cys) causes widespread severe lysosome pathology (hypopigmentation, organomegaly, and delayed myelination and development, "HOD syndrome"), but no osteopetrosis. We now describe two additional HOD individuals with the previously described p.Tyr715Cys and a novel p.Lys285Thr mutation, respectively. Both mutations decreased ClC-7 inhibition by PI(3,5)P and affected residues lining its binding pocket, and shifted voltage-dependent gating to less positive potentials, an effect partially conferred to WT subunits in WT/mutant heteromers. This shift predicts augmented pH gradient-driven Cl uptake into vesicles. Overexpressing either mutant induced large lysosome-related vacuoles. This effect depended on Cl/H-exchange, as shown using mutants carrying uncoupling mutations. Fibroblasts from the p.Y715C patient also displayed giant vacuoles. This was not observed with p.K285T fibroblasts probably due to residual PI(3,5)P sensitivity. The gain of function caused by the shifted voltage-dependence of either mutant likely is the main pathogenic factor. Loss of PI(3,5)P inhibition will further increase current amplitudes, but may not be a general feature of HOD. Overactivity of ClC-7 induces pathologically enlarged vacuoles in many tissues, which is distinct from lysosomal storage observed with the loss of ClC-7 function. Osteopetrosis results from a loss of ClC-7, but osteoclasts remain resilient to increased ClC-7 activity.
PubMed: 38838776
DOI: 10.1016/j.jbc.2024.107437 -
Journal of Pediatrics. Clinical Practice Mar 2024We present a newborn with transient generalized osteosclerosis and negative genetic workup. The etiology of this condition is unknown. Given overlapping radiologic signs...
We present a newborn with transient generalized osteosclerosis and negative genetic workup. The etiology of this condition is unknown. Given overlapping radiologic signs with severe forms of osteopetrosis, familiarity with this condition is crucial for correct diagnosis and management.
PubMed: 38827482
DOI: 10.1016/j.jpedcp.2024.200100 -
Tissue & Cell Jun 2024Tumor necrosis factor superfamily member 11 (TNFSF11), or receptor activator of nuclear factor-κB ligand (RANKL), is a crucial osteoclast-stimulating factor binding to...
Tumor necrosis factor superfamily member 11 (TNFSF11), or receptor activator of nuclear factor-κB ligand (RANKL), is a crucial osteoclast-stimulating factor binding to RANK on osteoclast membranes. Mouse models are powerful tools for understanding the genetic mechanisms of related diseases. Here, we examined the utility of Tnfsf11 mutation in mice for understanding the mechanisms of bone remodeling and dysmorphology. The Tnfsf11gum mouse, discovered in 2011 at Jackson Laboratory, was used to study the genetic landscape associated with TNFSF11 inactivation in bone marrow tissues. Tnfsf11 and Tnfsf11 mice were subjected to Micro-CT observation, ELISA analysis, histological evaluation, and massively-parallel mRNA sequencing (RNA-Seq) analysis. Tnfsf11 mice exhibited severe osteopetrotic changes in the bone marrow cavity, along with significantly lower serum RANKL levels and a reduced number of tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts in the bone marrow compared to those in Tnfsf11 mice. However, tooth eruption between Tnfsf11 and Tnfsf11 mice did not differ. Furthermore, genes involved in osteoblast proliferation and differentiation, including Gli1, Slc35b2, Lrrc17, and Junb were differentially expressed. Heterozygous mutation of TNFSF11 was also associated with a slightly increased expression of genes involved in osteoclast proliferation and differentiation, including Tcirg1, Junb, Anxa2, and Atp6ap1. Overall, we demonstrate that single gene mutations in Tnfsf11 cause bone resorption instability without significantly altering the genes related to osteoblast and osteoclast activity in the bone marrow cavity, thus establishing an optimal resource as an experimental animal model for bone resorption in bone biology research.
Topics: Animals; Osteopetrosis; RANK Ligand; Mice; Disease Models, Animal; Osteoclasts; Mutation
PubMed: 38776732
DOI: 10.1016/j.tice.2024.102412 -
Asian Journal of Surgery May 2024
PubMed: 38760215
DOI: 10.1016/j.asjsur.2024.05.048 -
The Journal of Craniofacial Surgery May 2024Osteopetrosis (OP) is a heterogeneous group of rare, heredity bone disorders with variable clinical features involving the bones of the body. OP is characterized by...
Osteopetrosis (OP) is a heterogeneous group of rare, heredity bone disorders with variable clinical features involving the bones of the body. OP is characterized by increased bone density, which is caused by aberrant osteoclast-mediated bone resorption. This syndromic disorder comes with a series of problems and, unless recognized and treated early, can lead to a multitude of further grave complications. We report a rare case of a female patient who reported chronic unhealed extraoral draining sinus present over the left submandibular region with pathologic fracture of the left mandibular angle, which, if, was diagnosed early with the identification of the osteopetrosis syndrome, could have been managed more conservatively.
PubMed: 38752749
DOI: 10.1097/SCS.0000000000010319 -
Calcified Tissue International Jul 2024Autosomal dominant osteopetrosis type 2 (ADO2) is a rare inherited bone disorder characterised by dense but brittle bones. It displays striking phenotypic variability,...
Autosomal dominant osteopetrosis type 2 (ADO2) is a rare inherited bone disorder characterised by dense but brittle bones. It displays striking phenotypic variability, with the most severe symptoms, including blindness and bone marrow failure. Disease management largely relies on symptomatic treatment since there is no safe and effective treatment. Most ADO2 cases are caused by heterozygous loss-of-function mutations in the CLCN7 gene, which encodes an essential Cl/H antiporter for proper bone resorption by osteoclasts. Thus, siRNA-mediated silencing of the mutant allele is a promising therapeutic approach, but targeting bone for first-in-human translation remains challenging. Here, we demonstrate the utility of silicon-stabilised hybrid lipid nanoparticles (sshLNPs) as a next-generation nucleic acid nanocarrier capable of delivering allele-specific siRNA to bone. Using a Clcn7 knock-in mouse model recapitulating one of the most common human ADO2 mutations and based on the 129S genetic background (which produces the most severe disease phenotype amongst current models), we show substantial knockdown of the mutant allele in femur when siRNA targeting the pathogenic variant is delivered by sshLNPs. We observed lower areal bone mineral density in femur and reduced trabecular thickness in femur and tibia, when siRNA-loaded sshLNPs were administered subcutaneously (representing the most relevant administration route for clinical adoption and patient adherence). Importantly, sshLNPs have improved stability over conventional LNPs and enable 'post hoc loading' for point-of-care formulation. The treatment was well tolerated, suggesting that sshLNP-enabled gene therapy might allow successful clinical translation of essential new treatments for ADO2 and potentially other rare genetic bone diseases.
Topics: Animals; Chloride Channels; Osteopetrosis; Mice; RNA, Small Interfering; Nanoparticles; Phenotype; Alleles; Bone and Bones; Disease Models, Animal
PubMed: 38733412
DOI: 10.1007/s00223-024-01222-3 -
JBJS Case Connector Apr 2024Two patients with osteopetrosis underwent conversion total hip arthroplasty (THA) after failure of internal fixation due to hip fractures. We experienced challenges,...
CASE
Two patients with osteopetrosis underwent conversion total hip arthroplasty (THA) after failure of internal fixation due to hip fractures. We experienced challenges, including difficulty of hardware removal, remaining of previous broken screws in the canal, difficulty in finding the femoral canal, and an intraoperative acetabulum fracture. Despite complications, both patients achieved satisfactory functional outcome after surgery at the latest follow-up.
CONCLUSION
Our cases showed that previous hip fracture and failed internal fixation make conversion THA more complex and unpredictable in patients with osteopetrosis. This in turn underscores the critical need for advanced preoperative planning, intraoperative flexibility, and meticulous postoperative care.
Topics: Humans; Arthroplasty, Replacement, Hip; Osteopetrosis; Female; Hip Fractures; Male; Middle Aged; Fracture Fixation, Internal; Aged
PubMed: 38728525
DOI: 10.2106/JBJS.CC.23.00583