Osteopetrosis: genetics, treatment and new insights into osteoclast function

Abstract

Osteopetrosis is a genetic condition of increased bone mass, which is caused by defects in osteoclast formation and function. Both autosomal recessive and autosomal dominant forms exist, but this Review focuses on autosomal recessive osteopetrosis (ARO), also known as malignant infantile osteopetrosis. The genetic basis of this disease is now largely uncovered: mutations in TCIRG1, CLCN7, OSTM1, SNX10 and PLEKHM1 lead to osteoclast-rich ARO (in which osteoclasts are abundant but have severely impaired resorptive function), whereas mutations in TNFSF11 and TNFRSF11A lead to osteoclast-poor ARO. In osteoclast-rich ARO, impaired endosomal and lysosomal vesicle trafficking results in defective osteoclast ruffled-border formation and, hence, the inability to resorb bone and mineralized cartilage. ARO presents soon after birth and can be fatal if left untreated. However, the disease is heterogeneous in clinical presentation and often misdiagnosed. This article describes the genetics of ARO and discusses the diagnostic role of next-generation sequencing methods. The management of affected patients, including guidelines for the indication of haematopoietic stem cell transplantation (which can provide a cure for many types of ARO), are outlined. Finally, novel treatments, including preclinical data on in utero stem cell treatment, RANKL replacement therapy and denosumab therapy for hypercalcaemia are also discussed.

Graphene‐Based MicroRNA Transfection Blocks Preosteoclast Fusion to Increase Bone Formation and Vascularization

“…Two important regulating factors, receptor activator of nuclear factor κB ligand (RANKL) and macrophage‐colony stimulating factor (M‐CSF) are necessary for OC differentiation and survival 2. Dysregulation of osteoclastogenesis can lead to various bone disorders and the most common one is osteoporosis 3, 4. According to the International Osteoporosis Foundation, more than 200 million people suffer from this disease worldwide 5.…”

A Case of Cytomegalovirus Infection in a Neonate with Osteopetrosis

“…Different genetic mutations described include those observed in TCIRG1 (encoding the a3 subunit of ruffled membrane), CLCN7, OSTM1, and PLEKHM1 3,4) .…”

Malignant Infantile Osteopetrosis: A Case Report

“…Kemik iliği açısından değerlendirildiğinde, osteoklastların zengin olduğu, intrinsik defektler nedeniyle fonksiyonunun bozuk olduğu osteopetrozlarda TCIRG1, CLCN7, OSTM1 mutasyonları gö-rülürken, osteoklastların az sayıda olduğu ya da olmadığı osteopetrozlarda RANK ve RANKL mutasyonları görülmektedir (10,11). Bunun önemi, RANKL mutasyonlarının hematopoetik kök hücre transplantasyonuna yanıt vermemesinden kaynaklanmaktadır.…”

“…Olgumuzun ayırıcı tanısında enfeksiyon hastalıkları, doğumsal metabolik hastalıklar dışlandı. Kök hücre transplantasyonu malign infantil osteopetrozun kesin tedavisidir (10,11). Tanı konulur konulmaz infant dönemde nörolojik bozukluklar ortaya çıkmadan HLA uygun kardeş donörden transplantasyon yapılmalıdır (15).…”