Abstract
Lamin A/C is a major constituent of the nuclear lamina implicated in a number of genetic diseases, collectively known as laminopathies. The most severe forms of laminopathies feature, among other symptoms, congenital scoliosis, osteoporosis, osteolysis or delayed cranial ossification.Importantly, specific bone districts are typically affected in laminopathies. Spine is severely affected in LMNA-linked congenital muscular dystrophy. Mandible, terminal phalanges and clavicles undergo osteolytic processes in progeroid laminopathies and Restrictive Dermopathy, a lethal developmental laminopathy. This specificity suggests that lamin A/C regulates fine mechanisms of bone turnover, as supported by data showing that lamin A/C mutations activate non-canonical pathways of osteoclastogenesis, as the one dependent on TGF beta 2.Here, we review current knowledge on laminopathies affecting bone and LMNA involvement in bone turnover and highlight lamin-dependent mechanisms causing bone disorders. This knowledge can be exploited to identify new therapeutic approaches not only for laminopathies, but also for other rare diseases featuring bone abnormalities.
Highlights
Lamins constitute a network of filamentous proteins, the nuclear lamina, underlying the inner nuclear membrane [1]
Bone disorders found in laminopathies are osteoporosis, osteolysis, delayed closure of cranial sutures and scoliosis, the latter being mostly found in congenital muscular dystrophies linked to LMNA [2, 5]
We demonstrated that monocytes subjected to farnesyl transferase inhibitor (FTI-277) treatment and mostly those subjected to AFCMe administration, differentiate towards the osteoclastic lineage more efficiently than untreated monocytes, in terms of number of multinucleated giant cells and mRNA expression of osteoclast-related genes [91]
Summary
Lamins constitute a network of filamentous proteins, the nuclear lamina, underlying the inner nuclear membrane [1]. The patient had a very early onset of bone disorders consisting of decreased spine and limb bone density, multiple spontaneous fractures, osteolysis of femoral head and cranial sutures still open at 15 years of age [40] These findings together suggest that patients with MAD due to ZMPSTE24 mutations have a more severe skeletal phenotype than those with LMNA mutations [17, 38, 40] (Table 1). A main feature of laminopathies with bone disorders is accumulation of toxic levels of prelamin A in cells This is observed in MADB , HGPS and MADA nuclei, where nuclear shape abnormalities, increase of prelamin A at the nuclear rim and chromatin disorganization occur (Figure 2). Since osteolysis appears to be a generalized feature of all MAD forms [111], antiresorptive therapy may be considered an option to prevent or delay irreversible bone deformities [112]
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