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Journal of Cell Science Feb 2024Microglia, professional phagocytic cells of the brain, rely upon the appropriate activation of lysosomes to execute their immune and clearance functions. Lysosomal...
Microglia, professional phagocytic cells of the brain, rely upon the appropriate activation of lysosomes to execute their immune and clearance functions. Lysosomal activity is, in turn, modulated by a complex network of over 200 membrane and accessory proteins that relay extracellular cues to these key degradation centers. The ClC-7 chloride (Cl-)-proton (H+) antiporter (also known as CLCN7) is localized to the endolysosomal compartments and mutations in CLCN7 lead to osteopetrosis and neurodegeneration. Although the functions of ClC-7 have been extensively investigated in osteoclasts and neurons, its role in microglia in vivo remains largely unexamined. Here, we show that microglia and embryonic macrophages in zebrafish clcn7 mutants cannot effectively process extracellular debris in the form of apoptotic cells and β-amyloid. Despite these functional defects, microglia develop normally in clcn7 mutants and display normal expression of endosomal and lysosomal markers. We also find that mutants for ostm1, which encodes the β-subunit of ClC-7, have a phenotype that is strikingly similar to that of clcn7 mutants. Together, our observations uncover a previously unappreciated role of ClC-7 in microglia and contribute to the understanding of the neurodegenerative phenotypes that accompany mutations in this channel.
Topics: Animals; Microglia; Membrane Proteins; Chlorides; Zebrafish; Protons; Phagocytes; Chloride Channels
PubMed: 38294065
DOI: 10.1242/jcs.261616 -
Radiology Case Reports Apr 2024Osteopetrosis is a heterogenous group of inheritable disorders which manifests as increased bone density and brittleness. The most common and mildest variant typically...
Osteopetrosis is a heterogenous group of inheritable disorders which manifests as increased bone density and brittleness. The most common and mildest variant typically presents in adulthood with bone pain and pathologic fractures, including spondylolysis. We present the case of an otherwise healthy, active 17-year-old male with a history of osteopetrosis and 1 year of chronic back pain, found to have multilevel (L1-L4) spondylolysis in the setting of severe diffuse bony sclerosis consistent with osteopetrosis. While single-level spondylolysis is an uncommon complication of osteopetrosis, multilevel spondylolysis in the pediatric population is extremely rare and the genetics of prior cases studies have not been reported. Spondylolysis should be considered as one of the types of fractures that may occur in patients with osteopetrosis.
PubMed: 38292800
DOI: 10.1016/j.radcr.2024.01.017 -
Case Reports in Ophthalmology 2024Osteopetrosis is a rare heritable disorder characterized by increased bone density resulting from osteoclast dysfunction. Major complications include bone fracture,...
INTRODUCTION
Osteopetrosis is a rare heritable disorder characterized by increased bone density resulting from osteoclast dysfunction. Major complications include bone fracture, osteomyelitis, anemia, and cranial nerve compression. Optic atrophy can occur due to compression of the optic nerve. Although osteomyelitis of the jaw is a common complication, it rarely occurs in the maxilla. Here, we report a case of a 74-year-old female with osteopetrosis who developed maxillary osteomyelitis, leading to orbital inflammation.
CASE PRESENTATION
She was referred to our clinic for 2 months of ptosis and swelling of the left eyelid and temporal region. Previous imaging revealed a left intraorbital occupying lesion, but a biopsy of the temporal subcutaneous tissue did not provide a definitive diagnosis. After 7 months, she presented with severe temporal swelling and purulent discharge. Upon examination, maxillary osteomyelitis resulting from caries of the upper jaw was observed. Treatment with oral antibiotics, drainage of the temporal skin fistula, and regular cleaning of the maxillary drainage improved her symptoms.
CONCLUSION
This is a rare case of maxillary osteomyelitis associated with osteopetrosis, causing orbital inflammation.
PubMed: 38288029
DOI: 10.1159/000536140 -
The Journal of Clinical Endocrinology... Jun 2024Autosomal dominant osteopetrosis (ADO) is a rare genetic disorder resulting from impaired osteoclastic bone resorption. Clinical manifestations frequently include...
CONTEXT
Autosomal dominant osteopetrosis (ADO) is a rare genetic disorder resulting from impaired osteoclastic bone resorption. Clinical manifestations frequently include fractures, osteonecrosis (particularly of the jaw or maxilla), osteomyelitis, blindness, and/or bone marrow failure. ADO usually results from heterozygous missense variants in the Chloride Channel 7 gene (CLCN7) that cause disease by a dominant negative mechanism. Variants in the T-cell immune regulator 1 gene (TCIRG1) are commonly identified in autosomal recessive osteopetrosis but have only been reported in 1 patient with ADO.
CASE DESCRIPTION
Here, we report 3 family members with a single heterozygous missense variant (p.Gly579Arg) in TCIRG1 who have a phenotype consistent with ADO. Three of 5 protein prediction programs suggest this variant likely inhibits the function of TCIRG1.
CONCLUSION
This is the first description of adult presentation of ADO caused by a TCIRG1 variant. Similar to families with ADO from CLCN7 mutations, this variant in TCIRG1 results in marked phenotype variability, with 2 subjects having severe disease and the third having very mild disease. This family report implicates TCIRG1 missense mutations as a cause of ADO and demonstrates that the marked phenotypic variability in ADO may extend to disease caused by TCIRG1 missense mutations.
Topics: Humans; Osteopetrosis; Mutation, Missense; Male; Female; Pedigree; Adult; Vacuolar Proton-Translocating ATPases; Phenotype; Middle Aged; Genes, Dominant
PubMed: 38261998
DOI: 10.1210/clinem/dgae040 -
Methods in Molecular Biology (Clifton,... 2024Osteoclasts are specialized cells that degrade bone and are essential for bone formation and maintaining bone homeostasis. Excess or deficient activity of these cells...
Osteoclasts are specialized cells that degrade bone and are essential for bone formation and maintaining bone homeostasis. Excess or deficient activity of these cells can significantly alter bone mass, structure, and physical strength, leading to significant morbidity, as in osteoporosis or osteopetrosis, among many other diseases. Protein phosphorylation in osteoclasts plays critical roles in the signaling pathways that govern the production of osteoclasts and regulate their bone-resorbing activity. In this chapter, we describe the isolation of mouse splenocytes and their differentiation into mature osteoclasts on resorptive (e.g., bone) and non-resorptive (e.g., plastic or glass) surfaces, examining matrix resorption by osteoclasts, immunofluorescence staining of these cells, and knocking out genes by CRISPR in the mouse osteoclastogenic cell line RAW264.7.
Topics: Animals; Mice; Osteoclasts; Osteogenesis; Bone Density; Cell Differentiation; Phosphoprotein Phosphatases
PubMed: 38147208
DOI: 10.1007/978-1-0716-3569-8_4 -
Impaired Autophagic Clearance with a Gain-of-Function Variant of the Lysosomal Cl/H Exchanger ClC-7.Biomolecules Dec 2023ClC-7 is a ubiquitously expressed voltage-gated Cl/H exchanger that critically contributes to lysosomal ion homeostasis. Together with its β-subunit Ostm1, ClC-7...
ClC-7 is a ubiquitously expressed voltage-gated Cl/H exchanger that critically contributes to lysosomal ion homeostasis. Together with its β-subunit Ostm1, ClC-7 localizes to lysosomes and to the ruffled border of osteoclasts, where it supports the acidification of the resorption lacuna. Loss of ClC-7 or Ostm1 leads to osteopetrosis accompanied by accumulation of storage material in lysosomes and neurodegeneration. Interestingly, not all osteopetrosis-causing mutations from patients are associated with a loss of ion transport. Some rather result in an acceleration of voltage-dependent ClC-7 activation. Recently, a gain-of-function variant, ClC-7, that yields larger ion currents upon heterologous expression, was identified in two patients with neurodegeneration, organomegaly and albinism. However, neither the patients nor a mouse model that carried the equivalent mutation developed osteopetrosis, although expression of ClC-7 induced the formation of enlarged intracellular vacuoles. Here, we investigated how, in transfected cells with mutant ClC-7, the substitution of this tyrosine impinged on the morphology and function of lysosomes. Combinations of the tyrosine mutation with mutations that either uncouple Cl from H counter-transport or strongly diminish overall ion currents were used to show that increased ClC-7 Cl/H exchange activity is required for the formation of enlarged vacuoles by membrane fusion. Degradation of endocytosed material was reduced in these compartments and resulted in an accumulation of lysosomal storage material. In cells expressing the ClC-7 gain-of-function mutant, autophagic clearance was largely impaired, resulting in a build-up of autophagic material.
Topics: Mice; Animals; Humans; Osteopetrosis; Gain of Function Mutation; Mutation; Lysosomes; Tyrosine; Chloride Channels
PubMed: 38136669
DOI: 10.3390/biom13121799 -
BMC Oral Health Nov 2023Osteopetrosis comprises a group of inherited disorders that are rare and result in abnormal bone structure. Bone remodeling is extremely inhibited because osteoclasts...
Successful complete oral rehabilitation of a patient with osteopetrosis with extensive pre-treatments, bone grafts, dental implants and fixed bridges: a multidisciplinary case report.
BACKGROUND
Osteopetrosis comprises a group of inherited disorders that are rare and result in abnormal bone structure. Bone remodeling is extremely inhibited because osteoclasts are nonfunctional or lacking. This condition causes overgrowth of bone with disappearance of the bone marrow, leading to aplastic anemia; obstruction of nerve passages in the skull leads to blindness and often hearing impairment. In most cases, osteopetrosis results in oral complications such as tooth deformation, hypomineralization, and delayed or absent tooth eruption. The only curative treatment is hematopoietic stem cell transplantation (HSCT). The main treatment of the oral complications during childhood and adolescence consists in protecting the erupted teeth against caries disease through prophylactic treatment aimed at optimal oral hygiene through frequent regular dental visits throughout life. Many patients with osteopetrosis require major oral rehabilitation to treat complications of the disease. Improved results of HSCT increase the likelihood that dental professionals will encounter patients with osteopetrosis.
CASE PRESENTATION
In this case report, we show that individuals with osteopetrosis who have severe oral complications can be treated successfully if they are treated for osteopetrosis at an early age. The boy had his dental care in pedodontics, and regular multidisciplinary meetings were held for future treatment planning. At the age of 15, he was then referred for rehabilitation. The initial evaluations revealed no further growth in the alveolar bone. The rehabilitation was done stepwise, with extraction of malformed and malpositioned teeth. Initially, the patient received a removable partial denture followed by reconstruction of the width of the alveolar process, titanium implants, temporary fixed bridges, and finally screw-retained titanium-ceramic bridges with titanium frames for the upper and lower jaws.
CONCLUSIONS
The three-year follow-up after loading indicated a stable marginal bone level and optimal oral hygiene as a result of frequent professional oral hygiene care. The patient showed no signs of symptoms from the temporomandibular joint and has adapted to the new jaw relation without any functional or phonetical issues.
Topics: Male; Adolescent; Humans; Dental Implants; Osteopetrosis; Titanium; Dental Caries; Tooth Abnormalities; Denture, Partial, Fixed; Dental Prosthesis, Implant-Supported
PubMed: 38017429
DOI: 10.1186/s12903-023-03707-3 -
Scientific Reports Nov 2023Osteoclasts uniquely resorb calcified bone matrices. To exert their function, mature osteoclasts maintain the cellular polarity and directional vesicle trafficking to...
Osteoclasts uniquely resorb calcified bone matrices. To exert their function, mature osteoclasts maintain the cellular polarity and directional vesicle trafficking to and from the resorbing bone surface. However, the regulatory mechanisms and pathophysiological relevance of these processes remain largely unexplored. Bone histomorphometric analyses in Ccr5-deficient mice showed abnormalities in the morphology and functional phenotype of their osteoclasts, compared to wild type mice. We observed disorganized clustering of nuclei, as well as centrosomes that organize the microtubule network, which was concomitant with impaired cathepsin K secretion in cultured Ccr5-deficient osteoclasts. Intriguingly, forced expression of constitutively active Rho or Rac restored these cytoskeletal phenotypes with recovery of cathepsin K secretion. Furthermore, a gene-disease enrichment analysis identified that PLEKHM1, a responsible gene for osteopetrosis, which regulates lysosomal trafficking in osteoclasts, was regulated by CCR5. These experimental results highlighted that CCR5-mediated signaling served as an intracellular organizer for centrosome clustering in osteoclasts, which was involved in the pathophysiology of bone metabolism.
Topics: Animals; Mice; Bone and Bones; Bone Matrix; Bone Resorption; Cathepsin K; Centrosome; Osteoclasts; Receptors, CCR5
PubMed: 38012303
DOI: 10.1038/s41598-023-48140-2 -
International Journal of Surgery Case... Dec 2023Osteopetrosis is a rare genetic disorder characterized by increased bone density. This condition is clinically manifested with a brittle intramedullary structure and...
INTRODUCTION
Osteopetrosis is a rare genetic disorder characterized by increased bone density. This condition is clinically manifested with a brittle intramedullary structure and reduced bone toughness, increasing the risk of fracture. A limited case has been reported on the management of physeal fracture in patients with osteopetrosis. The objective of this study is to report a rare osteopetrosis patient who sustains Salter-Harris II at the distal tibia with its long-term follow-up along with its literature review.
PRESENTATION OF CASE
We report a case of a four-year-old boy with an established a diagnosis of osteopetrosis brought by the parents to the emergency department after sustaining a fall while playing in the playground. Radiological examination revealed a Salter-Harris type II distal tibial fracture. The patient underwent closed reduction and fixation using the cannulated screw. 18-month postoperative patients have an uneventful healing.
DISCUSSION
Osteopetrosis is caused by impaired osteoclast function and differentiation, leading to impaired in remodelling. Salter-Harris type II distal tibial fracture can be treated by either closed reduction or open reduction. A closed reduction was performed successfully with cannulated screw in his patient.
CONCLUSION
There is a delayed union of fracture in osteopetrosis patient. This will increase the risk of displacement which will eventually resulted in growth disturbance. Delayed weight bearing and stable fixation is highly recommended.
PubMed: 38007865
DOI: 10.1016/j.ijscr.2023.109090 -
Journal of Biomechanical Engineering Feb 2024Sensitivity coefficients are used to understand how errors in subject-specific musculoskeletal model parameters influence model predictions. Previous sensitivity studies...
Sensitivity coefficients are used to understand how errors in subject-specific musculoskeletal model parameters influence model predictions. Previous sensitivity studies in the lower limb calculated sensitivity using perturbations that do not fully represent the diversity of the population. Hence, the present study performs sensitivity analysis in the upper limb using a large synthetic dataset to capture greater physiological diversity. The large dataset (n = 401 synthetic subjects) was created by adjusting maximum isometric force, optimal fiber length, pennation angle, and bone mass to induce atrophy, hypertrophy, osteoporosis, and osteopetrosis in two upper limb musculoskeletal models. Simulations of three isometric and two isokinetic upper limb tasks were performed using each synthetic subject to predict muscle activations. Sensitivity coefficients were calculated using three different methods (two point, linear regression, and sensitivity functions) to understand how changes in Hill-type parameters influenced predicted muscle activations. The sensitivity coefficient methods were then compared by evaluating how well the coefficients accounted for measurement uncertainty. This was done by using the sensitivity coefficients to predict the range of muscle activations given known errors in measuring musculoskeletal parameters from medical imaging. Sensitivity functions were found to best account for measurement uncertainty. Simulated muscle activations were most sensitive to optimal fiber length and maximum isometric force during upper limb tasks. Importantly, the level of sensitivity was muscle and task dependent. These findings provide a foundation for how large synthetic datasets can be applied to capture physiologically diverse populations and understand how model parameters influence predictions.
Topics: Humans; Models, Biological; Musculoskeletal System; Muscles; Upper Extremity; Lower Extremity; Muscle, Skeletal; Isometric Contraction
PubMed: 37978046
DOI: 10.1115/1.4064056