| First Author | Besio R | Year | 2023 |
| Journal | Matrix Biol | Volume | 120 |
| Pages | 43-59 | PubMed ID | 37178987 |
| Mgi Jnum | J:338934 | Mgi Id | MGI:7485592 |
| Doi | 10.1016/j.matbio.2023.05.002 | Citation | Besio R, et al. (2023) CaMKII inhibition due to TRIC-B loss-of-function dysregulates SMAD signaling in osteogenesis imperfecta. Matrix Biol 120:43-59 |
| abstractText | Ca(2+) is a second messenger that regulates a variety of cellular responses in bone, including osteoblast differentiation. Mutations in trimeric intracellular cation channel B (TRIC-B), an endoplasmic reticulum channel specific for K(+), a counter ion for Ca(2+)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 Ca(2+) 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 osteoblasts, explained the osteoblast malfunction. The reduced SMAD phosphorylation and nuclear translocation were mainly caused by alteration in Ca(2+) calmodulin kinase II (CaMKII)-mediated signaling and to a less extend by a lower TGF-beta reservoir. SMAD signaling, osteoblast differentiation and matrix mineralization were only partially rescued by TGF-beta 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. |
