Mice lacking the intracellular cation channel TRIC-B have compromised collagen production and impaired bone mineralization

Tric-b knockout mice serve as a model for studying the bone defects of osteogenesis imperfecta. The TRIC to building strong bones During bone development, osteoblasts secrete a collagen-rich matrix that is necessary for bone mineralization. Defects in collagen deposition cause osteogenesis imperfecta (OI), a disease characterized by brittle bones. Zhao et al. found that mice lacking Tric-b, which encodes a trimeric intracellular cation channel that localizes to the endoplasmic reticulum (ER), had bone defects similar to those of OI patients. Although osteoblasts in Tric-b knockout mice synthesized collagen, it accumulated inside the cells instead of being secreted. The accumulation of intracellular collagen deposits was associated with morphological and biochemical markers of ER stress, including severe dilation, excess Ca2+ in the ER, and impaired Ca2+ release from the ER. These findings suggest that TRIC-B is necessary to maintain ER homeostasis, thus enabling osteoblasts to secrete the large amounts of collagen required to build strong bones. The trimeric intracellular cation (TRIC) channels TRIC-A and TRIC-B localize predominantly to the endoplasmic reticulum (ER) and likely support Ca2+ release from intracellular stores by mediating cationic flux to maintain electrical neutrality. Deletion and point mutations in TRIC-B occur in families with autosomal recessive osteogenesis imperfecta. Tric-b knockout mice develop neonatal respiratory failure and exhibit poor bone ossification. We investigated the cellular defect causing the bone phenotype. Bone histology indicated collagen matrix deposition was reduced in Tric-b knockout mice. Osteoblasts, the bone-depositing cells, from Tric-b knockout mice exhibited reduced Ca2+ release from ER and increased ER Ca2+ content, which was associated with ER swelling. These cells also had impaired collagen release without a decrease in collagen-encoding transcripts, consistent with a defect in trafficking of collagen through ER. In contrast, osteoclasts, the bone-degrading cells, from Tric-b knockout mice were similar to those from wild-type mice. Thus, TRIC-B function is essential to support the production and release of large amounts of collagen by osteoblasts, which is necessary for bone mineralization.