Inflammatory milieu cultivated Sema3A signaling promotes chondrocyte apoptosis in knee osteoarthritis

Abstract

Osteoarthritis (OA) is the leading degenerative joint disease and featured by articular cartilage destruction, where chondrocyte apoptosis plays a critical role. Semaphorin-3A (Sema3A) has been implicated in OA chondrocyte physiology. In this study we aimed to uncover how Sema3A signaling is regulated in chondrocytes and investigate its role in OA chondrocyte survival. Here, we report that Sema3A and its receptor neuropilin-1 (Nrp1) are synchronously upregulated in cartilage chondrocytes of knee OA patients. Their expressions in chondrocytes could be induced by the stimulation of proinflammatory cytokines IL-1β and TNF-α and subsequent transcriptional activation orchestrated by C/EBPβ. The resulting excessive Sema3A signaling promotes chondrocyte apoptosis through impairing PI3K/Akt prosurvival signaling. These findings indicate a regulatory mechanism and a proapoptotic function of aberrant Sema3A signaling in OA chondrocytes, and suggest that targeting Sema3A signaling might interfere OA pathogenesis.

Role of Semaphorins in Immunopathologies and Rheumatic Diseases

“…In ATDC5 cells, Sema3A induced apoptosis in a phosphatidylinositide 3-kinase/protein kinase B (PI3K/PKB)-dependent manner. In human chondrocytes from OA patients, Sema3A inhibited the VEGF 165 -induced chondrocyte cloning, a process involved in the repair of the damaged cartilage [66,67]. These results suggest that Sema3A inhibition could be an interesting therapeutic target for the treatment of OA.…”

Oral administration of N-acetyl cysteine prevents osteoarthritis development and progression in a rat model

“…Articular chondrocytes are derived from mesenchymal stem cells and produce various extracellular matrix proteins (ECMs) such as proteoglycans and type II collagen, and function in shock absorption and enabling smooth movement of joints. Mild articular cartilage damage can repair itself due to chondrocytes’ regenerative activities such as chondrocyte cloning regulated by reversion-inducing cysteine-rich protein with Kazal motifs (RECK) 2,3 and semaphorin 3A 4–6 . However, if articular cartilage damage covers a large area or occurs continuously, repair is no longer possible due to the limited proliferation and repair capacity in chondrocytes, and damage becomes irreversible, leading to osteoarthritis.…”

Neuromodulation of bone: Role of different peptides and their interactions (Review)

“…A similar complexity for neuronal regulation of skeletal cell differentiation and function is observed for certain neurotransmitters (such as leptin and NPY) mediated through the activation of central receptors different from those in peripheral nerves (23,91,113,117). These neuronal signals also regulate physiological and pathological conditions of cartilage by affecting chondrocyte proliferation, secretion, adhesion and terminal differentiation (21,95,99,107,124) (Fig. 3).…”

“…Gomez et al (103) reported that Sema3A and Plexin A2 mRNA were expressed in the MC615 mouse chondrogenic cell line before the onset of neurovascular invasion during endochondral ossification. In OA cartilage, Sema3A and its receptor Nrp1 were found to be upregulated (21,107). Okubo et al (21) first described that Sema3A functions competitively or cooperatively with VEGF-165 in modulating chondrocyte cloning by binding to the common receptor Nrp-1.…”

“…It seems that temporospatial regulation of Sema3A expression could contribute to the appropriate mobilization of lesional chondrocytes and chondrocyte cloning, a sign of active repair of damaged cartilage in OA. However, Sun et al (107) revealed the detrimental effect of Sema3A in OA. In that study, the proapoptotic function of augmented Sema3A signaling through impairing PI3K/Akt prosurvival signaling was identified in OA chondrocytes, along with subsequent transcriptional activation orchestrated by CCAAT-enhancer-binding protein β.…”