Narrowed intervertebral disc (IVD) space is a characteristic of IVD degeneration. EP sclerosis is associated with IVD, however the pathogenesis of EP hypertrophy is poorly understood. Here, we employed two spine instability mouse models to investigate temporal and spatial EP changes associated with IVD volume, considering them as a functional unit. We found that aberrant mechanical loading leads to accelerated ossification and hypertrophy of EP, decreased IVD volume and increased activation of TGFβ. Overexpression of active TGFβ in CED mice showed a similar phenotype of spine instability model. Administration of TGFβ Receptor I inhibitor attenuates pathologic changes of EP and prevents IVD narrowing. The aberrant activation of TGFβ resulting in EPs hypertrophy-induced IVD space narrowing provides a pharmacologic target that could have therapeutic potential to delay DDD.Degenerative disc disease (DDD) is one of the most common musculoskeletal disorders that is associated with disability and absenteeism from work. Degeneration has been detected as early as teenage years and severe degeneration is found in 60% of 70-year olds 1,2 . DDD typically presents with back pain and imposes an enormous socio-economic burden, over $100 billion annually in the US alone. This cost exceeds the combined costs of stroke, respiratory infection, diabetes, coronary artery disease and rheumatoid disease 1,2 . Several factors have been implicated to cause DDD such as aging, genetic predisposition, toxic factors, metabolic disorders, low-grade infection, neurogenic inflammation and mechanical factors 3 . However, the pathogenesis of DDD under mechanical loading environment is not well known.Intervertebral disc (IVD) is composed of three parts: gel-like nucleus pulposus (NP) in the central compartment surrounded by an annulus fibrosis (AF) ring, and both cranial and caudal cartilage endplates (EPs) that attach the IVD inner ring to the adjacent vertebrae. EPs transmit mechanical loads produced by body weight and muscle activity between the bony vertebrae and soft tissue 4 . Moreover, EPs serve as a selective permeability barrier, allowing passage of small solutes, such as nutrient substances but impeding transport of larger solutes such as inflammatory factors 5 . Sclerosis of EPs change the mechanical property and impair diffusion and nutrient supply, thus accelerating IVD degeneration 5 . However, the originating mechanism of EP pathology is still not clearly understood.EPs undergo calcification and ossification and become sclerotic with aging 6 . We have previously found that excess activation of TGFβ causes sclerosis and angiogenesis of subchondral bone in the knee joint, which alters loading distribution on articular cartilage and is key in the pathogenesis of osteoarthritis (OA) 7,8 . Upregulation of TGFβ has been observed in calcified hypertrophic EPs of degenerative IVD 9 . Whether TGFβ is involved in EP sclerotic changes is unknown.In this study, we investigated temporal and spatial EP changes resulting from mechanical stress by...