Impaired Bone Formation in TRIC-B-Knockout Mice

Abstract

Osteogenesis imperfect (OI) is a heritable bone dysplasia characterized by bone fragility, but has divergent phenotypic manifestations, suggesting heterogeneous OI-responsible genes in the human genome. Most of OI cases result from defected type I collagen; structural mutations and altered post-translational modifications lead to its insufficient content, folding and trafficking errors, and also compromised matrix incorporation. Recently, a homozygous deletion mutation in the TRIC-B (also referred to as TMEM38B) locus has been identified in Saudi Arabic and Bedouin Israeli OI pedigrees. The OI mutant gene encodes a truncated TRIC-B protein lacking its C-terminal half, and is likely associated with severe impairment of TRIC-B channel activity in various cell types. However, pathological mechanism is still unknown in the OI pedigrees.The TRIC (trimeric intracellular cation) channel subtypes, namely TRIC-A and TRIC-B, form homotrimeric complexes to function as intracellular monovalent cation-specific channels. TRIC-A channels are predominantly expressed in muscle and brain, while TRIC-B channels are ubiquitously detected throughout excitable and non-excitable cell types. Based on our observations in knockout mice, TRIC channels seem to mediate, in part, counterion movements to support efficient Ca2+ release from the sarco/endoplasmic reticulum. Tric-b-knockout mice develop respiratory failure at birth, and the mutant alveolar epithelial cells exhibit compromised IP3R-mediated Ca2+ release and insufficient handling of surfactant lipids. In skeleton preparations from Tric-b-knockout neonates, semi-translucent parts were frequently detected in major bones, indicating impaired bone formation. Indeed, insufficient bone mineralization was confirmed by computed tomography imaging and histochemical analysis. RT-PCR experiments detected decreased expression of osteocalcin and RanklmRNAs as osteoblast makers in Tric-b-knockout femoral bones, suggesting the possibility that Tric-b deficiency may affect osteoblast functions. Therefore, Tric-b-knockout neonates provide a useful model for OI bearing the mutant TRIC-B gene.