Related Experiment Video
Updated: Sep 26, 2026
A RANKL-based Osteoclast Culture Assay of Mouse Bone Marrow to Investigate the Role of mTORC1 in Osteoclast Formation
Published on: March 15, 2018
Osteoclast morphology in autosomal recessive malignant osteopetrosis due to a TCIRG1 gene mutation
Elisabeth Bruder1, Thomas Stallmach, Karin Peier
1Pediatric Pathology Section, Department of Pathology, University Hospital Zurich, Switzerland.
Insights
Bone marrow transplantation successfully treated a TCIRG1 gene mutation causing autosomal recessive osteopetrosis. Donor osteoclasts were observed, indicating active bone resorption before radiological changes.
Area of Science:
- Genetics
- Hematology
- Orthopedics
Background:
- Osteopetrosis is a rare genetic disorder characterized by defective osteoclast function, leading to impaired bone resorption and increased bone density.
- Malignant autosomal recessive osteopetrosis, often caused by mutations in the TCIRG1 gene (encoding the vacuolar H+-ATPase a3 subunit), presents in infancy with severe skeletal abnormalities and potential complications.
- Hematopoietic stem cell transplantation (HSCT) is a potential curative treatment for osteopetrosis, aiming to replace the defective osteoclast precursors with functional donor cells.
Observation:
- A 3-month-old infant with TCIRG1-associated autosomal recessive osteopetrosis underwent HLA-compatible bone marrow transplantation.
- Pre-transplant bone biopsies revealed immature bone trabeculae, absent medullary hematopoiesis, and functionally deficient osteoclasts lacking ruffled borders.
- Post-transplant biopsies demonstrated the presence of donor-derived osteoclasts exhibiting characteristic ruffled borders and intracytoplasmic mineral crystals, indicative of active bone resorption.
Findings:
- Successful engraftment of donor hematopoietic stem cells led to the development of functional osteoclasts.
- Morphological evidence of active bone resorption by donor osteoclasts was observed on biopsy.
- These findings suggest that HSCT can restore osteoclast function in TCIRG1-deficient osteopetrosis, even before radiological signs of bone remodeling are apparent.
Implications:
- Bone marrow transplantation is a viable therapeutic strategy for malignant autosomal recessive osteopetrosis due to TCIRG1 mutations.
- Morphological analysis of bone biopsies can serve as an early indicator of successful osteoclast engraftment and functional recovery post-transplantation.
- Genetic diagnosis and early intervention, such as HSCT, are crucial for improving outcomes in patients with osteopetrosis.
Abstract:
Bone biopsies were performed before and 7 weeks after transplantation of HLA-compatible bone marrow from the sister of a 3-month-old male infant with malignant autosomal recessive osteopetrosis due to a mutation in the TCIRG1 (ATP6i) gene. The first biopsy showed broad, immature bony trabeculae and no medullary hematopoiesis. Only few osteoclasts were present and electron microscopy showed absence of ruffled borders. The post transplant biopsy revealed donor osteoclasts with ruffled borders and intracytoplasmic mineral crystals as proof of active bone resorption that had not yet been detectable radiographically. Osteopetrosis is a genetically heterogeneous disease. Definition at the DNA-level will enable comparison of treatment strategies and prenatal diagnosis. As shown in this patient, the autosomal recessive form caused by a TCIRG1 gene mutation may be amenable to bone marrow transplantation. Activity of donor osteoclasts can be demonstrated morphologically on biopsy, before bone remodeling becomes evident radiologically.
Related Concept Videos
01:20The Retinoblastoma Gene
The first-ever tumor suppressor gene called Rb was identified in retinoblastoma - a rare eye tumor in children. In inherited forms of the disease, a child inherits one defective copy of the Rb gene, which predisposes them to retinoblastoma. However,...
01:20The Retinoblastoma Gene
The first-ever tumor suppressor gene called Rb was identified in retinoblastoma - a rare eye tumor in children. In inherited forms of the disease, a child inherits one defective copy of the Rb gene, which predisposes them to retinoblastoma. However,...
01:31Osteoclasts in Bone Remodeling
01:12Loss of Tumor Suppressor Gene Functions
When the tumor suppressor genes develop mutations or are lost, cells start growing out of control, leading to cancer. However, a single functional copy of the tumor suppressor gene is enough for the cells to maintain their normal functions and cell...
01:12Loss of Tumor Suppressor Gene Functions
When the tumor suppressor genes develop mutations or are lost, cells start growing out of control, leading to cancer. However, a single functional copy of the tumor suppressor gene is enough for the cells to maintain their normal functions and cell...
01:05Cancer-Critical Genes II: Tumor Suppressor Genes
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...