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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 -
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 -
Asian Journal of Surgery May 2024
PubMed: 38760215
DOI: 10.1016/j.asjsur.2024.05.048 -
JBMR Plus May 2024The purpose of this study was to identify new independent significant SNPs associated with osteoporosis using data from the Taiwan Biobank (TWBB).
PURPOSE
The purpose of this study was to identify new independent significant SNPs associated with osteoporosis using data from the Taiwan Biobank (TWBB).
MATERIAL AND METHODS
The dataset was divided into discovery (60%) and replication (40%) subsets. Following data quality control, genome-wide association study (GWAS) analysis was performed, adjusting for sex, age, and the top 5 principal components, employing the Scalable and Accurate Implementation of the Generalized mixed model approach. This was followed by a meta-analysis of TWBB1 and TWBB2. The Functional Mapping and Annotation (FUMA) platform was used to identify osteoporosis-associated loci. Manhattan and quantile-quantile plots were generated using the FUMA platform to visualize the results. Independent significant SNPs were selected based on genome-wide significance ( < 5 × 10) and independence from each other (r < 0.6) within a 1 Mb window. Positional, eQTL(expression quantitative trait locus), and Chromatin interaction mapping were used to map SNPs to genes.
RESULTS
A total of 29 084 individuals (3154 osteoporosis cases and 25 930 controls) were used for GWAS analysis (TWBB1 data), and 18 918 individuals (1917 cases and 17 001 controls) were utilized for replication studies (TWBB2 data). We identified a new independent significant SNP for osteoporosis in TWBB1, with the lead SNP rs76140829 (minor allele frequency = 0.055, -value = 1.15 × 10). Replication of the association was performed in TWBB2, yielding a -value of 6.56 × 10. The meta-analysis of TWBB1 and TWBB2 data demonstrated a highly significant association for SNP rs76140829 (-value = 7.52 × 10). In the positional mapping of rs76140829, 6 genes (, , , , , ) were identified through chromatin interaction mapping in mesenchymal stem cells.
CONCLUSIONS
Our GWAS analysis using the Taiwan Biobank dataset unveils rs76140829 in the gene as a key risk variant associated with osteoporosis. This finding expands our understanding of the genetic basis of osteoporosis and highlights the potential regulatory role of this SNP in mesenchymal stem cells.
PubMed: 38655459
DOI: 10.1093/jbmrpl/ziae028 -
European Journal of Medical Genetics Jun 2024Osteopetrosis refers to a group of related rare bone diseases characterized by a high bone mass due to impaired bone resorption by osteoclasts. Despite the high bone... (Review)
Review
Osteopetrosis refers to a group of related rare bone diseases characterized by a high bone mass due to impaired bone resorption by osteoclasts. Despite the high bone mass, skeletal strength is compromised and the risk of fracture is high, particularly in the long bones. Osteopetrosis was classically categorized by inheritance pattern into autosomal recessive forms (ARO), which are severe and diagnosed within the first years of life, an intermediate form and an autosomal dominant (ADO) form; the latter with variable clinical severity and typically diagnosed during adolescence or in young adulthood. Subsequently, the AD form was shown to be a result of mutations in the gene CLCN7 encoding for the ClC-7 chloride channel). Traditionally, the diagnosis of osteopetrosis was made on radiograph appearance alone, but recent molecular and genetic advances have enabled a greater fidelity in classification of osteopetrosis subtypes. In the more severe ARO forms (e.g., malignant infantile osteopetrosis MIOP) typical clinical features have severe consequences and often result in death in early childhood. Major complications of ADO are atypical fractures with delay or failure of repair and challenge in orthopedic management. Bone marrow failure, dental abscess, deafness and visual loss are often underestimated and neglected in relation with lack of awareness and expertise. Accordingly, the care of adult patients with osteopetrosis requires a multidisciplinary approach ideally in specialized centers. Apart from hematopoietic stem cell transplantation in certain infantile forms, the treatment of patients with osteopetrosis, has not been standardized and remains supportive. Further clinical studies are needed to improve our knowledge of the natural history, optimum management and impact of osteopetrosis on the lives of patients living with the disorder.
Topics: Osteopetrosis; Humans; Osteoclasts; Adult; Chloride Channels; Mutation
PubMed: 38593953
DOI: 10.1016/j.ejmg.2024.104936 -
JBMR Plus May 2024Mutations in cause osteopetrosis in humans and rats. The germline and osteoclast conditional deletions of gene in mice lead to defective osteoclast bone resorption and...
Mutations in cause osteopetrosis in humans and rats. The germline and osteoclast conditional deletions of gene in mice lead to defective osteoclast bone resorption and increased trabecular bone mass without overt abnormalities in other organs. As an adaptor protein, pleckstrin homology and RUN domain containing M1 (PLEKHM1) interacts with the key lysosome regulator small GTPase RAB7 via its C-terminal RUBICON homologous (RH) domain. In this study, we have conducted a structural-functional study of the PLEKHM1 RH domain and RAB7 interaction in osteoclasts in vitro. The single mutations of the key residues in the Plekhm1 RH predicted from the crystal structure of the RUBICON RH domain and RAB7 interface failed to disrupt the Plekhm1-Rab7 binding, lysosome trafficking, and bone resorption. The compound alanine mutations at Y949-R954 and L1011-I1018 regions decreased Plekhm1 protein stability and Rab7-binding, respectively, thereby attenuated lysosome trafficking and bone resorption in osteoclasts. In contrast, the compound alanine mutations at R1060-Q1068 region were dispensable for Rab7-binding and Plekhm1 function in osteoclasts. These results indicate that the regions spanning Y949-R954 and L1011-I1018 of Plekhm1 RH domain are functionally important for Plekhm1 in osteoclasts and offer the therapeutic targets for blocking bone resorption in treatment of osteoporosis and other metabolic bone diseases.
PubMed: 38586475
DOI: 10.1093/jbmrpl/ziae034 -
International Journal of Surgery Case... Apr 2024Osteopetrosis is a rare hereditary disease that can be transmitted in an autosomal recessive or autosomal dominant.
INTRODUCTION
Osteopetrosis is a rare hereditary disease that can be transmitted in an autosomal recessive or autosomal dominant.
CASE REPORT
Here, we report a case of trochanteric fracture in an 18-year-old boy with an anatomical plate. At the last follow-up, 24 months after surgery, the fracture had healed well, and the patient was not restricted in his activities.
DISCUSSION
Osteopetrosis is a rare bone disease that is mainly caused by osteoclast dysfunction. It results from a remodelling defect that leads to hypermineralization of the skeleton, resulting in bone fragility. Both surgical and nonsurgical management have advantages and disadvantages. Thus, open reduction and anatomic plate fixation remain effective management modalities for trochanteric fractures in osteopetrosis patients.
CONCLUSION
For our patient and as described in the literature, the complication rate decreases as some principles are respected with better consolidation of the osteoporotic fracture.
PubMed: 38513419
DOI: 10.1016/j.ijscr.2024.109568 -
Orthopedic Reviews 2024Osteopetrosis, a rare condition arising from osteoclast dysfunction, is characterised by increased bony density and obliteration of the intramedullary canal. While total...
Osteopetrosis, a rare condition arising from osteoclast dysfunction, is characterised by increased bony density and obliteration of the intramedullary canal. While total knee arthroplasty (TKA) is preferred for osteoarthritic patients with osteopetrosis, inherent disease characteristics pose surgical challenges. This article presents a patient with osteopetrosis treated with robotic arm-assisted TKA (RA-TKA). This approach provided precise bone resection, obviates the need for intramedullary guides, minimizes saw disposal, and reduces surgical duration, with satisfactory short-term outcomes. RA-TKA may be an effective treatment for osteoarthritis in patients with osteopetrosis.
PubMed: 38435436
DOI: 10.52965/001c.94238