CaMKII inhibition due to TRIC-B loss-of-function dysregulates SMAD signaling in osteogenesis imperfecta

Ca2+ is a second messenger that regulates a variety of cellular responses in bone, including osteoblast differ-entiation. Mutations in trimeric intracellular cation channel B (TRIC-B), an endoplasmic reticulum channel specific for K+, a counter ion for Ca2+flux, affect bone and cause a recessive form of osteogenesis imperfecta (OI) with a still puzzling mechanism. Using a conditional Tmem38b knock out mouse, we demonstrated that lack of TRIC-B in osteoblasts strongly impairs skeleton growth and structure, leading to bone fractures. At the cellular level, delayed osteoblast differentiation and decreased collagen synthesis were found consequent to the Ca2+ imbalance and associated with reduced collagen incorporation in the extracellular matrix and poor mineralization. The impaired SMAD signaling detected in mutant mice, and validated in OI patient osteo-blasts, explained the osteoblast malfunction. The reduced SMAD phosphorylation and nuclear translocation were mainly caused by alteration in Ca2+ calmodulin kinase II (CaMKII)-mediated signaling and to a less extend by a lower TGF-b reservoir. SMAD signaling, osteoblast differentiation and matrix mineralization were only partially rescued by TGF-b treatment, strengthening the impact of CaMKII-SMAD axes on osteoblast function. Our data established the TRIC-B role in osteoblasts and deepened the contribution of the CaMKII-SMAD signaling in bone.(c) 2023 Elsevier B.V. All rights reserved.

Automated summary

Ca2+ is a second messenger that regulates cellular responses in bone, and deficiency of TRIC-B causes bone growth and structural problems, leading to bone fractures. This is associated with imbalances in Ca2+, delayed osteoblast differentiation, and decreased collagen synthesis.