Bone biology: insights from osteogenesis imperfecta and related rare fragility syndromes

Abstract

The limited accessibility of bone and its mineralized nature have restricted deep investigation of its biology. Recent breakthroughs in identification of mutant proteins affecting bone tissue homeostasis in rare skeletal diseases have revealed novel pathways involved in skeletal development and maintenance. The characterization of new dominant, recessive and X‐linked forms of the rare brittle bone disease osteogenesis imperfecta (OI) and other OI‐related bone fragility disorders was a key player in this advance. The development of in vitro models for these diseases along with the generation and characterization of murine and zebrafish models contributed to dissecting previously unknown pathways. Here, we describe the most recent advances in the understanding of processes involved in abnormal bone mineralization, collagen processing and osteoblast function, as illustrated by the characterization of new causative genes for OI and OI‐related fragility syndromes. The coordinated role of the integral membrane protein BRIL and of the secreted protein PEDF in modulating bone mineralization as well as the function and cross‐talk of the collagen‐specific chaperones HSP47 and FKBP65 in collagen processing and secretion are discussed. We address the significance of WNT ligand, the importance of maintaining endoplasmic reticulum membrane potential and of regulating intramembrane proteolysis in osteoblast homeostasis. Moreover, we also examine the relevance of the cytoskeletal protein plastin‐3 and of the nucleotidyltransferase FAM46A. Thanks to these advances, new targets for the development of novel therapies for currently incurable rare bone diseases have been and, likely, will be identified, supporting the important role of basic science for translational approaches.

Positive airway pressure therapy for obstructive sleep apnea in patients with Osteogenesis imperfecta: a prospective pilot study

“…Osteogenesis imperfecta (OI) is a group of rare genetic disorders, in which mutations impair normal synthesis, assembly, folding, posttranslational modification, secretion, or structure of type I collagen. The succedent detriment of collagen-rich tissues leads to typical clinical manifestations, such as bone fragility, hyperextensibility of ligaments, short stature, hearing impairment, and a tendency to progressive skeletal deformity of long bones, spine and cranial base [1,2]. Phenotypic classification of OI into five types covers a severity range from mild non-deforming (type I) to severe (type III) and lethal (type II) [3].…”

Diversity and bioactivity of fungi associated with the marine sea cucumber Holothuria poli : disclosing the strains potential for biomedical applications

“…The isolates biotechnological potential was investigated as their ability to synthetize metabolites for pharmaceutical applications. Investigated targets were the cytotoxicity against an hepatic cancer cell line (HepG2) and the bioactivity towards stem cell to promote their differentiation into bone or cartilage cell progenitors (Alves et al 2011;Besio et al 2019aBesio et al , 2019b.…”

Zebrafish: A Resourceful Vertebrate Model to Investigate Skeletal Disorders

“…The haploid zebrafish genome has 25 chromosomes containing 1.7 billion base pairs (4). Various forward and reverse genetic approaches have been applied to generate mutant lines that mimic many different human diseases, including skeletal diseases ranging from secondary osteoporosis (OP) to rare disorders such as osteogenesis imperfecta (OI) (12)(13)(14)(15)(16)(17)(18)(19)(20). A major benefit of zebrafish is the simplicity of combining mutant and transgenic lines that express fluorescent reporter proteins under the control of responsive elements for signaling pathways or promoters of cell-type-specific markers.…”