Three main hypotheses of PLS3-related osteogenesis imperfecta mechanisms have emerged (Figure 1D): (1) insufficient mineralization by osteoblasts (Fahiminiya et al., 2014), (2) increased bone resorption by osteoclasts (Neugebauer et al., 2018), and (3) dysregulation of osteocyte mechanosensing leading to misbalance between bone resorption and formation (Van Dijk et al., 2013). The gene discussed is PLS3; the disease is osteogenesis imperfecta.