Bone Abstracts

Objectives: A common feature of nearly all forms of osteogenesis imperfecta (OI) is a hypermineralized bone matrix. Null mutations in SERPINF1, encoding the potent antiangiogenic factor PEDF, lead to type VI OI with excessive osteoid formation, abnormal osteoblast-osteocyte development and increased matrix mineralization. Recently, atypical type VI OI has been delineated, caused by a loss-of-function mutation (p.S40L) in IFITM5 the causative gene for type V OI. The 6 cases reported to date have very severe OI, normal PEDF serum levels, but, similar to OI type VI, reduced PEDF secretion by osteoblasts. To gain further insights into the bone material properties, vascularization and thus pathophysiology of atypical type VI OI, we investigated a new knock-in (KI) mouse model carrying a leucine substitution for the BRIL p.Serine42 residue.

Methods: We analyzed longitudinal sections of distal femurs of 8 weeks-old heterozygous male mutants (KI, n=10) and wild-types (WT, n=9) using quantitative backscattered electron imaging (qBEI). Bone mineralization density distribution (BMDD) was measured in cancellous metaphyseal- and midshaft cortical bone. Osteocyte lacunae sections (OLS) were characterized in cortical bone. Structural histomorphometric parameters were evaluated in cancellous bone. We used X-ray microcomputed tomography (micro-CT) to evaluate vascularization in the femoral third trochanter.

Results: qBEI revealed that bone matrix mineralization was markedly increased in KI compared to WT cancellous (CaPeak: +2.38%, P=0.0331) and cortical bone (CaPeak: +2.81%, P=0.0085; CaMean: +2.48%, P=0.0023; CaWidth: +11.24%, P<0.0001, CaHigh: +51%, P=0.0027). We further observed in KI mice an increased OLS density (+23.11%, P<0.0001) and decreased OLS mean area and perimeter (−20.25%, P<0.0001; −13%, P<0.0001, respectively) versus WT. Histomorphometry revealed no changes of mineralized BV/TV, BS/TV, Tb.N and Tb.Th between the two genotypes. Micro-CT analyzes yielded increased pore volume/bone volume in KI (+14.28%, P=0.044) mirroring increased vascularity.

Conclusion: Our new mouse model for atypical type VI OI has elevated bone matrix mineralization and altered osteocyte lacunae characteristics similar to those of type VI OI. The increased bone vascular volume is consistent with defective PEDF secretion in bone as reported in affected patients. Further analysis of osteoblasts function and osteoid formation will provide additional insights in atypical OI type VI.

Disclosure: The authors declared no competing interests.