SAT-386 - Severe Osteoporotic Phenotype in Secisbp2 Deficiency

Objective: SECISBP2 deficient children manifest a consistent phenotype of severely delayed bone age and growth delay, and the long-term skeletal phenotype in this defect is unknown. The CreER Secisbp2 inducible conditional knockout (iCKO) mice with Secisbp2 deficiency induced at postnatal day P35 manifest global deficiency in selenoprotein synthesis, replicate the characteristic serum thyroid function tests and other phenotypes reported in patients with SECISBP2 defects. Both intracellular thyroid hormone (TH) availability and antioxidative protection are altered in SECISBP2 deficiency. The skeleton is an exquisitely sensitive T3-target tissue, and increased levels of reactive oxygen species (ROS) in the bone are known to be deleterious to normal bone physiology.

Methods: Ten-weeks-old Secisbp2 iCKO mice of both sexes and corresponding Wt littermates underwent static and dynamic histomorphometry studies of the bones.

Results: Body composition studies in Secisbp2 iCKO mice reveal significant reduced bone mass, both at the femur and in the whole body. On X-ray microradiography, the femurs and vertebrae have significantly lower bone mineral content, and femurs but not vertebrae are significantly shorter in Sbp2 iCKO mice compared to Wt littermates. Micro-CT analysis of trabecular bone shows reduced number and thickness of trabeculae with reduced trabecular volume, a more ‘porous’ trabecular bone overall, but normal mineral density in Secisbp2 iCKO mice of both sexes compared to respective Wt littermates. In biomechanical testing, these findings translate as significantly reduced femur strength and stiffness for Secisbp2 iCKO mice in the 3-point bend testing, with the cortical bone being thinner. Similarly, in vertebrae compression testing, the fewer and thinner trabeculae of Secisbp2 iCKO mice are less able to sustain load in compression and demonstrate significantly reduced vertebral strength. Furthermore, plasma bone turnover marker P1NP at 9-weeks was significantly decreased, while histomorphometry with osteoclast TRAP analysis performed at 16-weeks showed increased osteoclast number and surface in Secisbp2 deficient mice of both sexes.

Discussion: Secisbp2 deficient mice have a severe osteoporotic phenotype with uncoupling of bone remodeling and evidence of decreased osteoblastic bone formation as well as increased osteoclastic bone resorption. The abnormal tissue TH availability alone does not explain this severe phenotype. These findings highlight important roles of selenoproteins in maintaining bone mass, with contributions from the impaired TH metabolism as well as the increased ROS, and putative contributions from selenoproteins other than ROS. The syndrome of SECISBP2 deficiency represents a unique opportunity to understand selenoprotein biology relevant to health and disease.

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