High level of endothelin-1 contributes to subchondral bone disturbance in knee osteoarthritis

Abstract

Knee osteoarthritis (OA) is a pervasive degenerative joint disease and a prominent cause of disability in the elderly population. Hypertension is a common comorbid condition in knee OA, and increasing evidence has supported the role of the vasoconstrictor endothelin-1 (ET-1) in OA pathogenesis and progression. The hypothesis is that high level of vascular ET-1 is a shared pathomechanistic factor between OA and comorbid hypertension. To examine the impact of vascular ET-1 level on subchondral bone disturbances in relation to hypertension, a cohort of knee OA patients was recruited. Plasma ET-1 level and subchondral bone microstructure were examined using enzyme-linked immunosorbent assay (ELISA) and micro computed tomography (micro-CT). High plasma ET-1 level in our cohort of knee OA patients was associated with coexisting hypertension after adjusting the patients’ age, gender, body mass index and severity of

OA, and hypertensive OA patients displayed more porous subchondral bone plate and more sclerotic trabeculae. To examine the in vitro impact ET-1 on gene expressions of osteoblasts, tissue culture of OA and healthy osteoblasts was performed. In OA osteoblasts, the expression of EDN1 was found to correlate with COL1A1 and COL1A2 expression. Exogenous treatment of ET-1 stimulate healthy osteoblasts to increase production of the inflammatory cytokines IL-1β and matrix metalloproteinases (MMPs) responsible for degrading extracellular matrices, as well as the higher ratio of COL1A1 to COL1A2 expression, mimicking the gene expression pattern of OA osteoblasts. To investigate the impact of vascular ET-1 on subchondral bone in vivo, transgenic ET-1 overexpressing (TET) mice model with endothelial cell-specific ET-1 overexpression was used. The microstructure of subchondral bone was examined using micro-CT. TET mice exhibited the more porous subchondral bone plate and more sclerotic trabeculae, a similar pattern of subchondral bone disturbances found in hypertensive OA patients. All in all, elevation of vascular ET-1 level was found to be associated with comorbid hypertension and induce subchondral bone disturbance in the form of more pronounced perforation of subchondral bone plate, as well as more sclerotic subchondral trabecular bone. This is likely due to the stimulatory effects of high level of ET-1 that shifts the osteoblasts to a pathologically activated phenotype that promotes remodelling and sclerosis.