CD274 Knockout Promotes Bone Formation and Reduces Osteoclast Activity

Osteoporosis is a systemic disease characterized by decreased bone density, and deterioration in the micro-architectural remodelling of bone tissue, leading to an increased susceptibility to bone fractures. One molecule implicated in bone metabolism is Programmed Death Ligand 1 (PD-L1), a pharmacologically targetable immune-checkpoint molecule encoded by the gene Cd274. The aim of this study was to investigate the bone phenotype of Cd274 knockout (KO) mice at 26 weeks of age compared to C57BL/6J control wildtype mice on radiological, histological and biomechanical level. The cortical wall thickness and cortical volume increased, and the trabecular space decreased significantly in both femur and tibia of Cd274 KO mice. Moreover, there was a significant increase in BV/TV and trabecular volume of lumbar vertebrae of Cd274 KO mice. Yield load, stiffness, anorganic amount increased and organic amount decreased significantly in femoral bones of Cd274 KO mice. Additionally, there was a significantly higher number of osteocytes and lower number of osteoclasts in both humerus and lumbar vertebra of Cd274 KO mice. The findings demonstrate that constitutive knockout of Cd274 was associated with significantly increased bone mass and strength. These results—obtained in healthy, skeletally mature constitutive knockout mice—indicate an improved bone phenotype in the absence of Cd274 and thus contrast with previous studies that associate disruption of the PD-1/PD-L1 axis, including immune checkpoint inhibitor therapy, with bone loss and increased fracture risk. Further studies, particularly in dedicated osteoporosis models, are required to elucidate the influence of CD274 on bone metabolism before translational conclusions can be drawn.