Pathogenesis Of Osteopetrosis Research Articles

The synergistic role of Pu.1 and Fms in zebrafish osteoclast-reducing osteopetrosis and possible therapeutic strategies

Osteoclasts are bone resorption cells of myeloid origin. Osteoclast defects can lead to osteopetrosis, a genetic disorder characterized by bone sclerosis for which there is no effective drug treatment. It is known that Pu.1 and Fms are key regulators in myelopoiesis, and their defects in mice can lead to reduced osteoclast numbers and consequent osteopetrosis. Yet how Pu.1 and Fms genetically interact in the development of osteoclasts and the pathogenesis of osteopetrosis is still unclear. Here, we characterized pu.1G242D;fmsj4e1 double-deficient zebrafish, which exhibited a greater deficiency of functional osteoclasts and displayed more severe osteopetrotic symptoms than the pu.1G242D or fmsj4e1 single mutants, suggesting a synergistic function of Pu.1 and Fms in the regulation of osteoclast development. We further demonstrated that Pu.1 plays a dominant role in osteoclastogenesis, whereas Fms plays a dominant role in osteoclast maturation. Importantly, treatment with the drug retinoic acid significantly relieved the different degrees of osteopetrosis symptoms in these models by increasing the number of functional osteoclasts. Thus, we report the development of valuable animal models of osteopetrosis, and our results shed light on drug development for antiosteopetrosis therapy.

Case Report of Clinical Vignette: Osteopetrosis.

Osteopetrosis is a connective tissue disorder resulting from abnormally dense bone predisposing patients to fracture. The clinical pattern of fractures across time and space as well as suggestive radiographic findings usually raises diagnostic suspicion. Multiple genetic mutations resulting in dysfunctional osteoclasts have been implicated in the pathogenesis of osteopetrosis with variable inheritance patterns. In severe cases, usually inherited in an autosomal recessive pattern, the medullary cavity important in the production of normal blood cell progenitors is replaced by defective endochondral bone, leading to pancytopenia and consequential extramedullary hematopoiesis. This is a case report from a patient presenting to Naval Medical Center San Diego, a large Military Treatment Facility constituting a regional referral center for Navy Medicine West and serving approximately 250,000 eligible patients with more than 6,200 military and civilian staff. The genetic analysis was performed by Connective Tissue Gene Tests (CTGT) using the CTGT Osteopetrosis NextGen sequencing panel, consisting of 13 genes associated with osteopetrosis. A literature review was performed using PUBMED and Google Scholar to identify information on osteopetrosis and mutation implications. We present a 19-year-old male with clinical osteopetrosis resulting from compound heterozygosity of several mutated alleles within the PLEKHM1 gene, which is important to endosomal and lysosomal vesicular function. To date, most mutations discovered involve genes coding for intracellular enzymes, like carbonic anhydrase, or cell surface transporters, such as the osteoclast H+-ATPase proton pump and the chloride channel, engaged in the acidification of bone at the interface of the osteoclastic ruffled border and the bone matrix. This case represents one of the few reports of inherited defects within the PLEKHM1 gene, resulting in defective osteoclastic ruffled border formation and consequential inadequate bone resorption. This patient's lack of hematologic deficiencies and survival into adulthood portend an improved long-term prognosis and may infer prognostic insight in future cases with similar genetic abnormalities. In patients presenting with skeletal abnormalities and pathologic fractures in early adulthood, the clinician should consider osteopetrosis as a potential explanatory mechanism. Genetic characterization can elucidate cellular pathophysiology and potentially guide treatment modalities. Patients are typically managed with lifestyle adjustments limiting traumatic fracture and antiresorptive medications, typified by the bisphosphonate class. Since osteoclasts derive from a hematopoietic precursor, the only definitive curative therapy present is hematopoietic stem cell transplant. In the future, novel genomic level modulation may confer the ability to correct underlying point mutations and spare individuals from the morbidity associated with bone marrow transplant.

Therapy of malignant infantile osteopetrosis

A case of juvenile osteopetrosis in a 10-year-old girl, including the skeletal, hematologic, and neurologic features, is described. Ankylosis of cementum to bone was evident in histologic sections, providing a possible explanation for the delayed or impaired eruption of teeth. A summary of the literature on the pathogenesis of osteopetrosis is presented.

Intérêt de l'étude in vitro des précurseurs ostéoclastiques dans un cas d'ostéopétrose infantile sévère traité par greffe médullaire

Background. — Pathogenesis of osteopetrosis is still debated. Testing the ability of osteoclastic progenitors to support the proliferation of functional cells may be useful in understanding pathogenesis. Case report and methods. — A diagnosis of osteopetrosis was made in a girl 1 month-old, born to consanguuineous parents. Bone marrow transplantation was uneffective at the age of 3 months but a second engraftment was successful at 5 months. Unfortunately, the patient died from severe thrombocytopenia at the age of 8 months. Long-term cultures of mononuclead cells from the patient's blood were performed before and after the bone marrow transplantation, with or without growth factors such as vitamin D3, IL-6 and IL-1. Similar studies were made from the patient's marrow obtained after transplantation; all results were compared with those obtained after culturing control cells from cord blood umbilical. Results. — Production of osteoclastic cells was mild in peripheral blood cultures: it was inpatient in bone marrow cultures in presence of growth factors. Conclusion. — These results suggest that osteopetrosis in our patient resulted from an intrinsic defect in progenitors of osteoclasts.

Osteopetrosis: A case report including gross and microscopic findings in the mandible at autopsy

A case of juvenile osteopetrosis in a 10-year-old girl, including the skeletal, hematologic, and neurologic features, is described. Ankylosis of cementum to bone was evident in histologic sections, providing a possible explanation for the delayed or impaired eruption of teeth. A summary of the literature on the pathogenesis of osteopetrosis is presented.

Osteosclerosis, a recessive skeletal mutation on chromosome 19 in the mouse.

Osteosclerosis (oc) is an osteopetrotic mutation in the mouse inherited as an autosomal recessive on chromosome 19. Affected animals (oc/oc) exhibit the characteristic radiologic and histologic hallmarks of osteopetrosis including a generalized increase in skeletal density and absence of marrow cavities. Most die within three weeks after birth. Osteoclasts are cytologically abnormal by light microscopy in that they do not have cytoplasmic vacuoles. Presumptive evidence of rickets in this mutation includes thick cartilagenous growth plates and excessive osteoid. Extensive extramedullary hemopoiesis occurs in the liver and spleen of mutants. This unique constellation of features suggests that the oc mutation is a valuable model in which to investigate the pathogenesis of osteopetrosis.

Osteoclast populations in congenital 0steopetrosis: Additional evidence of heterogeneity

Osteopetrosis is a metabolic bone disease characterized by excessive accumulation of skeletal mass due to a reduction in bone resorption. The pathogenesis of osteopetrosis is reduced osteoclast function. Reports of osteoclast numbers in several mammalian mutations exhibiting osteopetrosis have shown them to be increased, decreased, or normal in numbers. The present investigation quantitated the osteoclast populations and examined the cytology of osteoclasts by light microscopy in calvarial and tibial sites in one rabbit and two mouse mutations and compared them with their normal littermates. Our observations show that osteoclast numbers are, depending: on the particular mutation, increased, decreased, or comparable to those found in normal littermates. In each mutation, however, osteoclasts fail to exhibit the cytoplasmic vacuolization next to bone surfaces seen in normal osteoclasts. These data provide additional evidence of heterogeneity in the congenital mammalian osteopetroses and suggest that these mutations may be significant sources of new information about the biology of osteoclasts.

Osteopetrosis: A scanning electron microscopic study

Scanning electron microscopic investigation was conducted with bone in a case of osteopetrosis by comparing it with normal cortical bone. The fractured surface of the ostepetrotic bone was devoid of the orderly constructed lamellar haversian system seen in normal bone. It was occupied by a massive smooth cartilaginous matrix containing scattered rough areas of abnormal ossification. Tortuous channels were randomly distributed and corresponded to the abortive marrow spaces. The presence of many irregular facture lines reflected the fragility of the bone. The findings support the concept of defective remodeling in the pathogenesis of osteopetrosis and provide a further explanation for the abnormal fragility of bone in osteopetrosis.

Pathogenesis of osteopetrosis in the microphthalmic mouse: reduced bone resorption.

Bone resorption, stimulated by injection of parathyroid extract, was measured in vivo in microphthalmic mice as the rate of release of 3H from bone after incorporation of 3H-proline. Bone resorption in these mice, which inherit osteopetrosis, was less than 10% of the in normal litermates. Autoradiography confirmed the reduction in removal of radioactive bone matrix and in bone growth in microphthalmic mice. The ability of these mice to raise the serum calcium concentration in response to PTE was also reduced. These results, that bone resorption is reduced in microphthalmic mice, are discussed in relation to the pathogenesis and cure of the disease.

Immunological defect and its correction in the osteopetrotic mutant rat.

Congenital osteopetrosis in the mutant rat "op" is accompanied by early atrophy of the thymus gland. The response of thymocytes to concanavalin A and phytohemagglutinin P was greatly diminished at age 28 days, even before pronounced thymic atrophy could be detected. The response of spleen cells to mitogens that stimulate thymus-derived (T) and bone-marrow-derived (B) cells was diminished as early as 35 days of age. A single injection of a suspension of normal bone marrow, which cures osteopetrosis, increased thymus weight and restored the normal responses of both thymus and spleen to various mitogens. These results add further support to the hypothesis that the thymus is involved in the pathogenesis of osteopetrosis.

Pathogenesis of osteopetrosis in the ia rat: reduced bone resorption due to reduced osteoclast function.

AbstractOsteopetrosis, a skeletal condition characterized by excessive accumulation of bone, is an inherited disease in man, rats and mice. In ia rats the condition undergoes spontaneous permanent remission beginning 30 to 50 days after birth, in contrast to the disease in mice and men. Thus, the ia rat offers a unique opportunity to analyze factors suspected of causing the skeletal condition.In the present investigation bone formation and bone resorption have been measured at various ages in ia rats and normal littermates. Bone matrix formation, measured by 3H‐proline uptake, was decreased slightly during the first three postnatal weeks and elevated slightly thereafter. Bone resorption, stimulated by injection of parathyroid extract, was determined in vivo as the rate of release of 3H from bone after incorporation of 3H‐proline. Bone resorption was reduced 20% at two weeks and elevated 20% by three weeks. Administration of parathyroid extract or thyroxine, or a deficiency of thyrocalcitonin produced by thyroidectomy (supplemented with thyroxine), did not hasten remission. An abnormally high cytoplasmic concentration of acid phosphatase activity was observed in ia osteoclasts during the first two weeks. The skeletal signs of spontaneous remission, appearing between 30 and 50 days after birth, were preceded by a normal response of the serum calcium to exogenous parathyroid extract, by increased bone resorption and by a more normal cytoplasmic distribution of acid phosphatase activity during the third postnatal week.These observations are interpreted to indicate that the osteopetrotic condition of ia rats is not due to deficiencies of parathyroid hormone or thyroxine or an excess of thyrocalcitonin but results from failure of osteoclasts to respond to stimuli promoting resorption. Specifically, these cells seem able to synthesize but not release normal amounts of the lysosomal enzyme acid phosphatase.

Pathogenesis of Osteopetrosis: A Comparison of Human and Animal Spectra

Pathogenesis of Osteopetrosis: A Comparison of Human and Animal Spectra