UCSF

The temporomandibular joint (TMJ) is one of the most frequently used joints in the human body, acting like a sliding hinge to connect the jawbone to the skull. Temporomandibular joint disorders (TMD) are dysregulations of the TMJ structure and function, prevailing in about 31% of the US population. One of the contributing causes of TMD is the degeneration of matrices, which are mediated by chondrocytes in the TMJ cartilage. The TMJ cartilage is derived from mesenchymal cells that differentiate into chondrocytes, forming the core of the cartilage. The p75 neurotrophin receptor (p75NTR), a single membrane-spanning protein in the tumor necrosis factor receptor superfamily, is a low-affinity receptor capable of binding all neurotrophins. Previous studies have demonstrated the role of p75NTR in the regulation of the mouse alveolar bone development and mineralization potential of ectomesenchymal stem cells (EMSCs). Studies have shown that global p75NTR deletion in mice have caused the mice to lose the ability to produce TMJ cartilage, concluding that p75NTR is required for TMJ chondrocyte differentiation and proliferation. Further investigation is required to delineate the role of p75NTR in chondrogenesis and its downstream signaling pathways, with an emphasis on identifying the receptor’s impact on cartilage-related genes and cellular mechanisms. Understanding the various target cells and genes that exist in the TMJ will help further our study of the role of p75NTR in the TMJ and enhance our therapeutic advances of TMDs. This study utilized a comprehensive suite of molecular techniques across wildtype (WT) and p75NTR knock-out (KO) mice, including RNA sequencing, network analysis, Alcian Blue staining, and Quantitative Real Time Polymerase Chain Reaction (qRT-PCR). We analyzed gene expression related to the BDNF pathway, cartilage markers, and critical signaling pathways potentially modulated by p75NTR. RNA sequencing and network analysis identified downregulation of BDNF pathway genes critical for protein folding and extracellular matrix organization in KO mice. Alcian Blue staining validated chondrogenic differences, revealing increased proteoglycan content in the presence of BDNF. qRT-PCR confirmed downregulation of most BDNF genes as well as cartilage marker genes, including Ihh, Aggrecan, Sox9, and types II collagen in KO mice, implying a pivotal role for p75NTR in cartilage synthesis and integrity. Furthermore, qRT-PCR results indicated a significant reduction in the expression of Akt, PI3k, and mTOR genes in KO mice, while Jun expression remained unchanged, suggesting a complex cascade of relationships downstream of p75NTR. The findings highlight the significant role of p75NTR in the regulation of genes and pathways critical to cartilage formation. The downregulation of key signaling molecules associated with p75NTR suggests a broad involvement of this receptor in cellular homeostasis. The study provides valuable insights into the molecular effects of p75NTR absence, setting the stage for potential therapeutic interventions in cartilage repair and neurodegenerative disorders.