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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 -
Cureus Feb 2024Idiopathic osteosclerosis (IO) is described as a localized radiopacity of unknown etiology. Also known as dense bone islands, enostoses, bone scar, or focal periapical...
Idiopathic osteosclerosis (IO) is described as a localized radiopacity of unknown etiology. Also known as dense bone islands, enostoses, bone scar, or focal periapical osteopetrosis, it is generally clinically asymptomatic and appears round, elliptical, or irregular in shape on a radiograph. The internal structure is usually homogenous. It should be distinguished from condensing osteitis and other alveolar bone-related radiopacities. This condition may cause changes in tooth position or interfere with orthodontic treatment. Two cases of IO involving the maxilla and mandible are highlighted. Both patients were females and presented with complaints of malocclusion and desired orthodontic correction. One case was detected incidentally on routine radiographic examination of the patient. In contrast, the other case presented as an expansile lesion lingual to the left mandibular first molar and second premolar. Radiographically, both lesions appeared as well-defined radiopaque masses with no surrounding radiolucent rim; the maxillary lesion was irregular in shape, while the mandibular lesion was elliptical. Both patients underwent orthodontic treatment without any adverse sequelae. The clinical and radiographic findings are discussed to facilitate the diagnosis of radiopacities of jaws. Usually asymptomatic and of no clinical significance, IO may occasionally induce root resorption, traumatic occlusion, traumatic/pathologic migration of teeth, and inhibit eruption of teeth. Though orthodontic tooth movement through areas of IO can be undertaken, the rate of tooth movement may be slower due to higher trabecular bone density. Lower force levels are warranted to avoid adverse effects like root resorption and bone hyalinization.
PubMed: 38435170
DOI: 10.7759/cureus.53426 -
Journal of Immunology (Baltimore, Md. :... Apr 2024Arthritis causes Fos-like 2 (Fosl2) inactivation, and various immune cells contribute to its pathogenesis. However, little is known about the role of Fosl2 in...
Arthritis causes Fos-like 2 (Fosl2) inactivation, and various immune cells contribute to its pathogenesis. However, little is known about the role of Fosl2 in hematopoiesis and the possible pathological role of Fosl2 inactivation in the hematopoietic system in arthritis. In this study, we show that Fosl2 maintains hematopoietic stem cell (HSC) quiescence and differentiation while controlling the inflammatory response via macrophages. Fosl2-specific deletion in the hematopoietic system caused the expansion of HSCs and myeloid cell growth while affecting erythroid and B cell differentiation. Fosl2 inactivation enhanced macrophage M1 polarization and stimulated proinflammatory cytokines and myeloid growth factors, skewing HSCs toward myeloid cell differentiation, similar to hematopoietic alterations in arthritic mice. Loss of Fosl2 mediated by Vav-iCre also displays an unexpected deletion in embryonic erythro-myeloid progenitor-derived osteoclasts, leading to osteopetrosis and anemia. The reduced bone marrow cellularity in Vav-iCreFosl2f/f mice is a consequence of the reduced bone marrow space in osteopetrotic mice rather than a direct role of Fosl2 in hematopoiesis. Thus, Fosl2 is indispensable for erythro-myeloid progenitor-derived osteoclasts to maintain the medullary cavity to ensure normal hematopoiesis. These findings improve our understanding of the pathogenesis of bone-destructive diseases and provide important implications for developing therapeutic approaches for these diseases.
Topics: Animals; Mice; Arthritis; Bone Marrow Failure Disorders; Cell Differentiation; Hematopoiesis; Hematopoietic Stem Cells; Osteopetrosis; Fos-Related Antigen-2
PubMed: 38380993
DOI: 10.4049/jimmunol.2300592 -
Journal of Molecular Medicine (Berlin,... Apr 2024Osteocalcin (OC) is the most abundant non-collagenous and osteoblast-secreted protein in bone. It consists of two forms such as carboxylated OC (cOC) and... (Review)
Review
Current knowledge of bone-derived factor osteocalcin: its role in the management and treatment of diabetes mellitus, osteoporosis, osteopetrosis and inflammatory joint diseases.
Osteocalcin (OC) is the most abundant non-collagenous and osteoblast-secreted protein in bone. It consists of two forms such as carboxylated OC (cOC) and undercarboxylated OC (ucOC). While cOC promotes bone mineralization and increases bone strength, ucOC is regarded an endocrinologically active form that may have several functions in multiple end organs and tissues. Total OC (tOC) includes both of these forms (cOC and ucOC) and is considered a marker of bone turnover in clinical settings. Most of the data on OC is limited to preclinical studies and therefore may not accurately reflect the situation in clinical conditions. For the stated reason, the aim of this review was not only to summarize current knowledge of all forms of OC and characterize its role in diabetes mellitus, osteoporosis, osteopetrosis, inflammatory joint diseases, but also to provide new interpretations of its involvement in the management and treatment of aforementioned diseases. In this context, special emphasis was placed on available clinical trials. Significantly lower levels of tOC and ucOC could be associated with the risk of type 2 diabetes mellitus. On the contrary, tOC level does not seem to be a good indicator of high bone turnover status in postmenopausal osteoporosis, osteoarthritis and rheumatoid arthritis. The associations between several pharmacological drugs used to treat all disorders mentioned above and OC levels have also been provided. From this perspective, OC may serve as a medium through which certain medications can influence glucose metabolism, body weight, adiponectin secretion, and synovial inflammation.
Topics: Humans; Diabetes Mellitus, Type 2; Osteocalcin; Osteopetrosis; Osteoporosis; Joint Diseases; Biomarkers
PubMed: 38363329
DOI: 10.1007/s00109-024-02418-8 -
Cureus Jan 2024Osteopetrosis is an uncommon and inherited disorder. Some disease-specific characteristics, such as diffuse osteosclerosis and a high incidence of fractures, may...
Osteopetrosis is an uncommon and inherited disorder. Some disease-specific characteristics, such as diffuse osteosclerosis and a high incidence of fractures, may potentially affect postoperative rehabilitation. This report presents a case of successful rehabilitation early after total hip arthroplasty for osteopetrosis. A 56-year-old Japanese man, who was diagnosed with osteopetrosis at the age of 11, underwent total hip arthroplasty in the right hip. Full weight-bearing was allowed on the day after the operation; the postoperative rehabilitation program was proceeded based on a standard program as done after total hip arthroplasty for osteoarthritis. A shoe lift in the left leg was used in supervised walking training to correct the imbalanced alignment due to leg length discrepancy. The patient could walk independently with a cane 17 days after the operation. Three weeks after the operation, the patient demonstrated comfortable and maximal walking speed of 1.11 and 1.34 m/s, respectively, and maximal hip abductor muscle strength of 3.96 kgf・m, both of which were better than those before the operation. There were no adverse events during the postoperative rehabilitation course. These findings suggest the safety and efficacy of standard rehabilitation programs after total hip arthroplasty even in individuals with osteopetrosis. In addition, it may be important to consider the whole-body condition in the rehabilitation of individuals with osteopetrosis.
PubMed: 38357069
DOI: 10.7759/cureus.52293 -
Nature Communications Feb 2024Osteoclasts are over-activated as we age, which results in bone loss. Src deficiency in mice leads to severe osteopetrosis due to a functional defect in osteoclasts,...
Osteoclasts are over-activated as we age, which results in bone loss. Src deficiency in mice leads to severe osteopetrosis due to a functional defect in osteoclasts, indicating that Src function is essential in osteoclasts. G-protein-coupled receptors (GPCRs) are the targets for ∼35% of approved drugs but it is still unclear how GPCRs regulate Src kinase activity. Here, we reveal that GPR54 activation by its natural ligand Kisspeptin-10 (Kp-10) causes Dusp18 to dephosphorylate Src at Tyr 416. Mechanistically, Gpr54 recruits both active Src and the Dusp18 phosphatase at its proline/arginine-rich motif in its C terminus. We show that Kp-10 binding to Gpr54 leads to the up-regulation of Dusp18. Kiss1, Gpr54 and Dusp18 knockout mice all exhibit osteoclast hyperactivation and bone loss, and Kp-10 abrogated bone loss by suppressing osteoclast activity in vivo. Therefore, Kp-10/Gpr54 is a promising therapeutic target to abrogate bone resorption by Dusp18-mediated Src dephosphorylation.
Topics: Animals; Mice; Osteoclasts; Kisspeptins; Receptors, G-Protein-Coupled; src-Family Kinases; Mice, Knockout; Bone Resorption; Receptors, Kisspeptin-1
PubMed: 38346942
DOI: 10.1038/s41467-024-44852-9 -
Stem Cell Research Apr 2024Infantile Malignant Osteopetrosis (IMO) is a rare, severe autosomal recessive form of osteopetrosis. Here, the peripheral blood mononuclear cells (PBMCs) extracted from...
Infantile Malignant Osteopetrosis (IMO) is a rare, severe autosomal recessive form of osteopetrosis. Here, the peripheral blood mononuclear cells (PBMCs) extracted from a patient with IMO carrying a compound heterozygous mutation in T cell immune regulator 1, ATPase H + transporting V0 subunit a3 (TCIRG1) gene (c.242delC; c.1114C > T) were successfully reprogrammed using Sendai virus encoding the four Yamanaka factors. The generated hiPSCs, IMO-hiPSCs, displayed typical embryonic stem cell-like morphology and were verified by expression of pluripotency markers such as OCT4, SOX2, NANOG, TRA-1-60 and SSEA4, as well as in vivo and in vitro differentiation into derivatives of three germ layers.
Topics: Humans; Induced Pluripotent Stem Cells; Osteopetrosis; Leukocytes, Mononuclear; Mutation; Genes, Homeobox; Cell Differentiation; Vacuolar Proton-Translocating ATPases
PubMed: 38335662
DOI: 10.1016/j.scr.2024.103330 -
Canadian Journal of Surgery. Journal... 2024Large-diameter head (LDH) total hip arthroplasty (THA) with a monobloc acetabular component improves hip stability. However, obtaining initial press-fit stability is...
Total hip arthroplasty with monobloc press-fit acetabular components and large-diameter bearings for atypical acetabula is safe: a consecutive case series of 125 hips with mean follow-up of 9 years.
BACKGROUND
Large-diameter head (LDH) total hip arthroplasty (THA) with a monobloc acetabular component improves hip stability. However, obtaining initial press-fit stability is quite challenging in atypical acetabula. The purpose of this study was to assess primary and secondary fixation of monobloc cups in atypical acetabula.
METHODS
In this consecutive case series, the local arthroplasty database was used to retrospectively identify patients with secondary osteoarthritis who underwent primary hip replacement with press-fit only LDH monobloc acetabular components between 2005 and 2018 and who had a minimum of 2 years of follow-up. Radiographic evaluation was performed at last follow-up, and patient-reported outcome measures (PROMs) were assessed with the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), the Forgotten Joint Score (FJS), and the Patient's Joint Perception (PJP) question.
RESULTS
One hundred and six LDH THAs and 19 hip resurfacings were included in the study. Preoperative diagnoses included hip dysplasia (36.8%), Legg-Calve-Perthes disease (32.0%), osteoarthritis with acetabular deficiency (17.6%), periacetabular osteotomy (8.0%), arthrodesis (4.0%), and osteopetrosis (1.6%). After a mean follow-up of 9.2 years, no aseptic loosening of the acetabular component was recorded nor observed on radiologic review. There were 13 (10.4%) revisions unrelated to the acetabular component fixation. The mean WOMAC and FJS scores were 9.2 and 80.9, respectively. In response to the PJP question, 49.4% of the patients perceived their hip as natural, 19.1% as an artificial joint with no restriction, 31.5% as an artificial joint with restriction, and none as a non-functional joint.
CONCLUSION
Primary press-fit fixation of monobloc acetabular components with LDH implanted in atypical acetabula led to secondary fixation in all cases with low revision and complication rates and great functional outcomes. With careful surgical technique and experience, systematic use of supplemental screw fixation is not essential in THA with atypical acetabula.
Topics: Humans; Arthroplasty, Replacement, Hip; Acetabulum; Follow-Up Studies; Retrospective Studies; Reoperation; Osteoarthritis; Hip Prosthesis; Treatment Outcome
PubMed: 38320777
DOI: 10.1503/cjs.014022 -
Global Pediatric Health 2024Carbonic anhydrase II deficiency is an extremely rare inborn error of metabolism that constitutes a triad osteopetrosis, renal tubular acidosis and intracerebral...
Carbonic anhydrase II deficiency is an extremely rare inborn error of metabolism that constitutes a triad osteopetrosis, renal tubular acidosis and intracerebral calcification. Unlike other subtypes of osteopetrosis, the presence of developmental delay and relative infrequency of skeletal fractures may not be a typical signs of symptoms indolent trajectory. This case report demonstrates a 11-year-old boy who had a bilateral midshaft tibial fracture despite low mechanism of injury. He was found to have severe respiratory distress with hypokalemia shortly after arriving to the emergency department venous blood gas (VBG) showed moderate metabolic acidosis. Potassium was corrected but he persistently had low potassium level despite frequent corrections. He was then started on sodium bicarbonate boluses. Whole exome sequencing (WES) was sent, and result was consistent with autosomal recessive osteopetrosis type III with renal tubular acidosis (RTA) evident by pathologic variant on gene confirming the diagnosis of carbonic anhydrase II (CA II) deficiency consistent with the unique Arabic mutation. Conversely, low mechanism of fracture injury in the context of severe form of fracture type should raise the concern of (CA II) deficiency especially in a pediatric patient who show no signs of developmental of cognitive delay.
PubMed: 38328522
DOI: 10.1177/2333794X241230873 -
Calcified Tissue International Apr 2024Autosomal Dominant Osteopetrosis type II (ADO2) is a rare bone disease of impaired osteoclastic bone resorption that usually results from heterozygous missense mutations...
Autosomal Dominant Osteopetrosis type II (ADO2) is a rare bone disease of impaired osteoclastic bone resorption that usually results from heterozygous missense mutations in the chloride channel 7 (CLCN7) gene. We previously created mouse models of ADO2 (p.G213R) with one of the most common mutations (G215R) as found in humans and demonstrated that this mutation in mice phenocopies the human disease of ADO2. Previous studies have shown that roflumilast (RF), a selective phosphodiesterase 4 (PDE4) inhibitor that regulates the cAMP pathway, can increase osteoclast activity. We also observed that RF increased bone resorption in both wild-type and ADO2 heterozygous osteoclasts in vitro, suggesting it might rescue bone phenotypes in ADO2 mice. To test this hypothesis, we administered RF-treated diets (0, 20 and 100 mg/kg) to 8-week-old ADO2 mice for 6 months. We evaluated bone mineral density and bone micro-architecture using longitudinal in-vivo DXA and micro-CT at baseline, and 6-, 12-, 18-, and 24-week post-baseline time points. Additionally, we analyzed serum bone biomarkers (CTX, TRAP, and P1NP) at baseline, 12-, and 24-week post-baseline. Our findings revealed that RF treatment did not improve aBMD (whole body, femur, and spine) and trabecular BV/TV (distal femur) in ADO2 mice compared to the control group treated with a normal diet. Furthermore, we did not observe any significant changes in serum levels of bone biomarkers due to RF treatment in these mice. Overall, our results indicate that RF does not rescue the osteopetrotic bone phenotypes in ADO2 heterozygous mice.
Topics: Humans; Animals; Mice; Phosphodiesterase 4 Inhibitors; Phenotype; Biomarkers; Osteoclasts; Bone Resorption; Osteopetrosis; Chloride Channels; Aminopyridines; Benzamides; Cyclopropanes
PubMed: 38300304
DOI: 10.1007/s00223-023-01180-2