Shcbp1 deficiency dampens chondrocyte viability and cartilage ECM homeostasis via disturbing coordination of Akt and Erk signal pathways

Abstract

Abstract Shcbp1 is known to participate in important signaling pathways related to growth and differentiation, but its role in cartilage has not been well understood. Our previous study found that the expression of Shcbp1 in cartilage is lower in patients with osteoarthritis. Herein, we aim to explore the roles of Shcbp1 and the underlying mechanisms in cartilage development and osteoarthritis pathogenesis. To investigate the role of Shcbp1, we deleted Shcbp1 at different stages in Col2a1-CreERT2;Shcbp1f/f mice through tamoxifen injection and analyzed the resulting phenotypes. We performed destabilization of the medial meniscus (DMM) after the deletion and then rescued Shcbp1 by knee cavity injection with adenovirus. We evaluated the osteoarthritis, extracellular matrix (ECM) homeostasis, and apoptosis using histology, immunohistochemistry, and TUNEL assay. We also detected Shcbp1 expression in knee joints from osteoarthritis patients and mice using immunohistochemistry. Additionally, we used molecular biology approaches to identify the downstream mechanism of Shcbp1. We found that Shcbp1 expression decreased during cartilage development. Embryonic Shcbp1 deletion caused postnatal lethality, shorter limbs, and chondrocyte malformation. Postnatal Shcbp1 deletion resulted in growth retardation, proliferation inhibition, and increased apoptosis. Mature deletion of Shcbp1 spontaneously led to osteoarthritis, and deletion of Shcbp1 in mice exacerbated osteoarthritis following DMM treatment. Importantly, local rescue of Shcbp1 ameliorated DMM-induced osteoarthritis. Shcbp1 expression was dramatically reduced in all the osteoarthritis-affected cartilage. The mechanism study showed that deletion of Shcbp1 decreased the ratio of Erk/Akt; conversely, rescue of Shcbp1 increased the ratio of Erk/Akt, similar to wild-type mice. Deletion of Shcbp1 played a detrimental role in ECM homeostasis and osteoarthritis pathogenesis by influencing the Erk and Akt signal pathways.