Mineralised bone properties in a child with recessive osteogenesis imperfecta type XIV and in a conditional Tmem38b...

OI type XIV is caused by variants in the TMEM38B gene, encoding for the ubiquitously expressed endoplasmic reticulum trimeric intracellular cation channel type B (TRIC-B), causing disruptions in calcium homeostasis and collagen synthesis. Patients with OI type XIV present with a highly variable clinical phenotype, ranging from asymptomatic to severe. We present here data from a 6 year clinical follow-up of two affected siblings and bone tissue characterisation obtained during corrective surgery from one of the patients, as well as tibiae from a novel Tmem38b conditional knockout murine model (Runx2-Cre; Tmem38b^fl/fl).

Clinical examinations of the patients include bone mineral density (BMD) measurements using dual-energy x-ray absorptiometry (DXA) scanning and gait analyses. Quantitative backscattered electron imaging (qBEI) was used to investigate bone mineralisation density distribution (BMDD) and osteocyte lacunae properties, and confocal laser scanning microscopy was used to quantify the osteocyte lacuno-canalicular network (OLCN) in both human and murine specimens.

Both patients (P1, P2) presented with muscular hypotension, fatigue, progression of lower limb deformities, and fractures. BMDD of the osteonal bone region of the tibia and fibula specimens obtained from P1 revealed no significant shift towards higher mineral content as seen in "classical" OI. Osteocyte lacunae porosity was elevated and analyses of the OLCN revealed a reduction in canalicular density and lacunar degree. Runx2-Cre; Tmem38b^fl/fl mice exhibited a very severe skeletal phenotype, with 10/12 of the tibiae showing evidence of fractures, bone deformations, or calluses. In contrast to the patient samples, both the cortex and metaphysis of mutant mice demonstrated a significant increase in the average mineral content (CaMean) and the peak of the distribution (CaPeak), as well as in osteocyte lacunae porosity (P < 0.0001), whereas canalicular density (P < 0.0001), and lacunar degree (P = 0.0004) were decreased.

While Runx2-Cre; Tmem38b^fl/fl mice exhibit hypermineralisation of the bone matrix, this is not apparent in bone specimens obtained from the OI type XIV patient. However, both human and murine bone tissue with absence of TRIC-B demonstrate the same abnormalities of the osteocyte lacunae porosity and osteocyte lacuno-canalicular network, indicating disruption to the OLCN which is likely a general hallmark of OI bone.