Cell Biology of Knee Joint Injuries: Early Mechanical Loading Perspective

Knee joint injuries, including those affecting the anterior cruciate ligament (ACL), meniscus, and cartilage, present complex challenges in sports medicine and orthopedics due to the intricate cellular and molecular mechanisms involved in tissue damage and repair. Understanding the molecular biology underpinning these processes is crucial for developing effective therapeutic and rehabilitation strategies. This systematic review investigates the impact of mechanical loading on the cellular responses during knee joint injury repair, with a particular focus on the molecular pathways involved in tissue regeneration. Mechanical loading plays a dual role, where controlled early loading can promote tissue repair, while excessive or inappropriate loading can exacerbate tissue damage. Fibroblasts, chondrocytes, and mesenchymal stem cells (MSCs) are central to the repair process, and their activation, proliferation, and differentiation are regulated by key molecular pathways. Upon injury, mechanotransduction pathways such as the integrin/FAK signaling axis are activated, which convert mechanical signals into biochemical responses that regulate cell adhesion, migration, and extracellular matrix (ECM) synthesis. Additionally, mechanosensitive ion channels like Piezo1 and TRPV4 modulate intracellular calcium levels, triggering downstream signaling cascades such as calmodulin/CaMKII, which regulate gene transcription and cellular responses to mechanical stress. The YAP/TAZ pathway, a critical component of the Hippo signaling pathway, responds to mechanical stimuli and regulates cell proliferation and ECM production in fibroblasts and chondrocytes. YAP/TAZ translocate to the nucleus in response to mechanical loading, where they interact with transcription factors such as TEAD, promoting the expression of genes involved in collagen synthesis and tissue repair. In parallel, growth factors like transforming growth factor-beta (TGF-β) and fibroblast growth factor (FGF) activate the TGF-β/Smad and PI3K/Akt signaling pathways, driving MSC differentiation into fibroblasts and chondrocytes, essential for ligament and cartilage repair. Mechanical loading also influences the inflammatory response at the injury site by modulating immune cell activity. Early mechanical loading can shift macrophages from a pro-inflammatory M1 phenotype to an anti-inflammatory M2 phenotype, mediated by growth factors such as TGF-β and interleukin-10 (IL-10). This phenotypic switch promotes tissue regeneration by enhancing ECM synthesis and resolving inflammation, which is crucial for long-term joint health. Matrix metalloproteinases (MMPs), regulated by NF-κB and MAPK pathways, play a role in ECM remodeling, where an imbalance between MMPs and their inhibitors (TIMPs) can lead to excessive matrix degradation, impeding tissue repair. Furthermore, Wnt/β-catenin signaling is activated in response to moderate mechanical loading, promoting chondrocyte proliferation and enhancing cartilage repair by upregulating type II collagen and aggrecan synthesis. However, dysregulation of Wnt signaling under excessive mechanical stress can lead to chondrocyte hypertrophy and cartilage degradation, contributing to osteoarthritis development. This review also explores emerging therapeutic strategies that leverage the molecular biology of knee joint repair, including biologics like platelet-rich plasma (PRP) and MSC-derived exosomes, which deliver bioactive molecules that activate critical regenerative pathways such as TGF-β/Smad and PI3K/Akt. Gene therapies targeting Wnt signaling or YAP/TAZ offer potential for enhancing tissue regeneration by modulating mechanotransduction and repair processes at the molecular level. In conclusion, the molecular biology of cellular responses to mechanical loading is central to knee joint repair following injuries. By understanding these processes and targeting specific molecular pathways, clinicians can optimize rehabilitation protocols and develop novel therapeutic approaches that enhance tissue regeneration, prevent chronic degeneration, and restore joint function. This comprehensive synthesis highlights the importance of integrating molecular insights into treatment strategies for ACL, meniscal, and cartilage injuries to improve patient outcomes.