Mechanism	Key Molecules & Pathways	Description / Biological Effects	Role in Cartilage Repair	References
1. Stem Cell Recruitment and Differentiation	- MSCs, TGF-β, BMPs (BMP-2, BMP-7), FGFs (FGF-18) - SMAD2/3, SMAD1/5/8, SOX9 - IGF-1, AKT, ERK - Wnt/β-catenin, Notch (crosstalk)	MSCs migrate in response to chemotactic gradients (cytokines, DAMPs). TGF-β activates SMAD2/3 and SOX9 for chondrogenesis, while BMPs engage SMAD1/5/8 to further induce collagen type II and proteoglycan synthesis. FGFs, especially FGF-18, promote chondrocyte proliferation and matrix production. IGF-1 supports anabolic activity.	Ensures that MSCs home to the injury site and differentiate into chondrocytes, laying down cartilage-specific extracellular matrix (ECM). Balances chondrocyte lineage commitment over osteogenic or adipogenic fates.	[@416796; @416797; @416803; @416804; @416805; @416806; @416807]
2. ECM Synthesis and Remodeling	- Collagen type II, Aggrecan - MMPs (MMP-13), ADAMTS-4/5 - TIMPs - SLRPs (Decorin, Biglycan) - Integrins (α5β1, αvβ3)	Newly differentiated chondrocytes produce collagen type II fibrils and proteoglycans (e.g., aggrecan). MMPs and aggrecanases degrade damaged ECM, while TIMPs inhibit excessive ECM breakdown. SLRPs orchestrate collagen fibril organization. Integrin signaling regulates cytoskeletal changes and gene expression for matrix upkeep.	Maintains mechanical integrity (tensile strength, compressive resilience). Balanced remodeling removes damaged ECM, integrates new matrix, and preserves healthy cartilage structure. Excessive catabolism (e.g., high MMP levels) or insufficient remodeling impairs repair outcomes.	[@416798; @416812; @416813; @416814; @416815; @416816; @416817; @416818; @416819]
3. Angiogenesis and Vascularization	- VEGF, VEGFR-1 (Flt-1), VEGFR-2 (KDR/Flk-1) - HIF-1α (hypoxia) - Angiopoietins (Ang-1, Ang-2), Tie-2 receptor - PDGF, bFGF (FGF-2) - Thrombospondins, Endostatin (anti-angiogenic)	Early vascularization provides nutrients and oxygen; VEGF upregulation under hypoxic conditions activates new vessel formation via PI3K–Akt, RAF–MEK–ERK. Ang-1 and Ang-2 regulate vessel stability and regression. Anti-angiogenic factors (e.g., endostatin) ensure eventual return to an avascular cartilage phenotype.	Supports initial nutrient delivery and waste removal to regenerating tissue. Transition to avascular state is crucial for hyaline cartilage formation. Persistent vascularization drives fibrocartilage production instead of stable, load-bearing cartilage.	[@416820; @416821; @416822; @416823; @416824; @416825; @416826; @416827; @416828; @416829; @416830]
4. Growth Factor Synergy and Crosstalk	- TGF-β/BMP cross-regulation - Wnt/β-catenin, Notch - FGF, IGF-1 - SMAD inhibitory loops (SMAD6/7), Noggin, Chordin, Follistatin	TGF-β and BMPs can activate overlapping SMAD pathways. Crosstalk with Wnt and Notch pathways influences cell fate decisions. Inhibitory SMADs and BMP antagonists prevent excessive cartilage or bone formation, ensuring balanced chondrogenesis. IGF-1 and FGFs add anabolic signals, promoting matrix deposition and cell proliferation.	Harmonizes the rate and extent of chondrocyte differentiation, preventing cartilage from undergoing premature ossification or from forming suboptimal fibrocartilage. Ensures stable, hyaline-like cartilage matrix over the course of repair.	[@416797; @416805; @416807]
5. Mechanotransduction	- Integrins (e.g., α5β1, αvβ3) - FAK (focal adhesion kinase), RhoA, Rac1 - TRPV4 (ion channel) - MAPK (ERK1/2, p38)	Chondrocytes sense mechanical loads through integrins at focal adhesions. FAK activation leads to downstream MAPK/ERK and p38 signaling, modulating cytoskeletal dynamics and gene transcription. Mechanosensitive ion channels like TRPV4 also trigger anabolic responses under physiological loading conditions.	Appropriate mechanical stress enhances chondrocyte proliferation, ECM synthesis (collagen type II, proteoglycans), and matrix organization. Excessive or abnormal loading can upregulate catabolic enzymes, hindering repair.	[@416799; @416808; @416818; @416819; @416830]
6. Inflammation Regulation	- IL-1, TNF-α, MMPs, ADAMTS - NF-κB pathway	Acute inflammation aids MSC recruitment and early remodeling. Persistent inflammation upregulates catabolic enzymes (MMPs, ADAMTS), degrading ECM and inhibiting chondrocyte metabolism. NF-κB amplifies cytokine production. Calibrating the immune response is critical for functional repair.	Moderates ECM destruction and promotes chondrocyte activity. Chronic inflammation disrupts cartilage integrity; controlled inflammation balances matrix turnover and new tissue integration.	[@416800; @416814; @416815]
7. Subchondral Bone Interaction	- Bone marrow cues, microdamage - TGF-β, BMPs (released from bone) - Cross-talk via vascular channels and cytokines	Subchondral bone provides mechanical support and releases molecular signals that diffuse into cartilage. Microdamage or sclerosis alters these signals, contributing to chronic inflammation and suboptimal cartilage regeneration.	A healthy subchondral bone niche fosters improved cartilage repair by stabilizing the tissue and providing growth factors that enhance chondrogenesis. Abnormal bone remodeling can degrade cartilage or impede regeneration.	[@416798; @416800]
8. Gene and Cell-Based Influences	- Viral/non-viral vectors (for TGF-β, IGF-1, SOX9) - RNAi, CRISPR/Cas9 to silence catabolic mediators - MicroRNA-based regulation (miR-140)	Gene transfer methods can increase local chondrogenic factor expression or block cartilage-degrading genes. Engineered stem cells may overexpress cartilage-specific signals or remain resistant to catabolic stimuli. MicroRNAs fine-tune anabolic/catabolic gene expression.	Enhances endogenous cartilage repair, directs MSCs toward stable chondrocyte differentiation, and limits ECM breakdown. Potential to produce more robust and durable cartilage akin to native tissue.	[@416801; @416802]