Genetics of osteopetrosis: Molecular insights and clinical implications

Abstract

The balance between bone resorption and formation is critical for bone and mineral homeostasis. The imbalance of this process leads to several bone diseases, including bone loss or excessive bone density. Osteopetrosis is a rare genetic disorder characterized by defective bone resorption due to impaired osteoclast function, resulting in excessive bone density, which paradoxically leads to a higher incidence of fractures. These fractures are difficult to heal due to impaired bone remodeling. Osteopetrosis manifests in autosomal dominant osteopetrosis (OPTA) and autosomal recessive osteopetrosis (OPTB) forms. OPTA is caused by heterozygous variations in genes such as low-density lipoprotein receptor-related protein 5 (LRP5) (affecting Wnt signaling), chloride voltage-gated channel 7 (CLCN7) (a chloride channel), and pleckstrin homology and RUN domain containing M1 (PLEKHM1) (involved in vesicular transport), resulting in osteosclerosis with variable skeletal complications. OPTB, caused by biallelic variants in genes such as T-cell immune regulator 1 (TCIRG1) (V-ATPase subunit), tumor necrosis factor superfamily member 11 (TNFSF11)/TNFRSF11A (osteoclast differentiation), CA2 (acid-base balance), and osteoclastogenesis Associated Transmembrane Protein 1 (OSTM1) (osteoclast maturation), presents with severe skeletal dysplasia, fractures, hematopoietic deficits, and neuropathies. Central to pathogenesis is the disruption of osteoclast acidification and resorption machinery. Genes such as TCIRG1, CLCN7, and CA2 are crucial for establishing the acidic microenvironment required for bone degradation. The TNFSF11/TNFRSF11A pathway, essential for osteoclast differentiation through nuclear factor-kappa B and MAPK signaling, highlights a therapeutic duality: Overactivity causes osteoporosis, while inactivating mutations lead to osteopetrosis. Next-generation sequencing enables variant detection, but genetic heterogeneity and modifiers complicate prognosis. Epigenetic regulators, including noncoding RNAs, further influence disease severity. Personalized medicine, which integrates genetic insights with novel therapies, holds promise, while early diagnosis and multidisciplinary care remain essential. Ongoing research into unresolved genetic and mechanistic factors is critical to optimizing treatment strategies.