Absence of TRIC-B from type XIV Osteogenesis Imperfecta osteoblasts alters cell adhesion and mitochondrial function – A multi-omics study

Milena Jovanovic, Apratim Mitra, Roberta Besio, Barbara Maria Contento, Ka Wai Wong, Alberta Derkyi, Michael To, Antonella Forlino, Ryan K. Dale, Joan C. Marini

Research output: Contribution to journalArticlepeer-review

Abstract

Osteogenesis Imperfecta (OI) is a heritable collagen-related bone dysplasia characterized by bone fractures, growth deficiency and skeletal deformity. Type XIV OI is a recessive OI form caused by null mutations in TMEM38B, which encodes the ER membrane intracellular cation channel TRIC-B. Previously, we showed that absence of TMEM38B alters calcium flux in the ER of OI patient osteoblasts and fibroblasts, which further disrupts collagen synthesis and secretion. How the absence of TMEM38B affects osteoblast function is still poorly understood. Here we further investigated the role of TMEM38B in human osteoblast differentiation and mineralization. TMEM38B-null osteoblasts showed altered expression of osteoblast marker genes and decreased mineralization. RNA-Seq analysis revealed that cell-cell adhesion was one of the most downregulated pathways in TMEM38B-null osteoblasts, with further validation by real-time PCR and Western blot. Gap and tight junction proteins were also decreased by TRIC-B absence, both in patient osteoblasts and in calvarial osteoblasts of Tmem38b-null mice. Disrupted cell adhesion decreased mutant cell proliferation and cell cycle progression. An important novel finding was that TMEM38B-null osteoblasts had elongated mitochondria with altered fusion and fission markers, MFN2 and DRP1. In addition, TMEM38B-null osteoblasts exhibited a significant increase in superoxide production in mitochondria, further supporting mitochondrial dysfunction. Together these results emphasize the novel role of TMEM38B/TRIC-B in osteoblast differentiation, affecting cell-cell adhesion processes, gap and tight junction, proliferation, cell cycle, and mitochondrial function.

Original languageEnglish
Pages (from-to)127-148
Number of pages22
JournalMatrix Biology
Volume121
DOIs
StatePublished - 1 Aug 2023
Externally publishedYes

Keywords

  • Cell adhesion
  • Mitochondrial fission/fusion
  • Osteoblast differentiation
  • Osteogenesis imperfecta
  • TMEM38B
  • TRIC-B

ASJC Scopus subject areas

  • Molecular Biology

Fingerprint

Dive into the research topics of 'Absence of TRIC-B from type XIV Osteogenesis Imperfecta osteoblasts alters cell adhesion and mitochondrial function – A multi-omics study'. Together they form a unique fingerprint.

Cite this