{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nCathepsin K is a highly potent cysteine protease central to skeletal homeostasis. In osteoclasts it degrades type I collagen and other matrix proteins during bone resorption, and its activity is tightly regulated by RANKL–NFATc1 signaling to ensure proper coupling of resorption and formation. Genetic ablation or pharmacological inhibition of cathepsin K in mice not only diminishes bone resorption but—for example by altering osteoclast‐derived signals such as sphingosine‐1‐phosphate or periostin—can stimulate new bone formation, improve trabecular and cortical bone mass, and even accelerate fracture healing. These findings, supported by studies of osteoclast and osteocyte targeted deletion, also explain clinical disorders such as pycnodysostosis and shed light on the osteoclast resorption cycle and its termination mechanisms."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "10"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its classical skeletal role, cathepsin K is increasingly recognized as an important mediator of immune and inflammatory processes. In autoimmune arthritis and periodontal disease models, inhibition or deletion of cathepsin K reduces inflammatory cytokine production, dampens Toll‐like receptor signaling, and limits joint and bone destruction. In parallel, tumor‐derived cathepsin K can interact with TLR4 on macrophages to promote an immunosuppressive, metastasis‐supporting microenvironment in colorectal cancer. These studies emphasize a function for cathepsin K not only in matrix degradation but also in shaping local immune responses in diverse pathological settings."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "11", "end_ref": "18"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the cardiovascular and metabolic arenas, cathepsin K participates in extracellular matrix remodeling that modulates vascular integrity and cardiac function. Endothelial exposure to disturbed shear stress can upregulate cathepsin K, contributing to arterial wall remodeling and plaque vulnerability; in turn, genetic deletion of cathepsin K protects mice against obesity‐associated cardiac dysfunction, pressure overload–induced hypertrophy, and age‐related decline in contractile performance. These studies underline the enzyme’s role beyond bone by implicating it in atherosclerosis, aneurysm formation, and stress‐related cardiomyocyte injury."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "19", "end_ref": "28"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nCathepsin K also contributes to soft tissue remodeling and fibrotic processes. Experimental models of pulmonary fibrosis demonstrate that aberrant cathepsin K activity influences collagen turnover and may modulate transforming growth factor‐β1 levels, thereby affecting fibroblast proliferation and matrix deposition. In addition, misdirected expression in non‐skeletal cells—for example, in tendon progenitor populations where deletion of Sufu in cathepsin K–expressing cells provokes heterotopic ossification—highlights the enzyme’s impact on pathological ossification. Finally, while the majority of the abstracts discussed above focus on cathepsin K, one study investigating the entire repertoire of mammalian β‐defensins revealed that almost all such peptides are preferentially expressed in the male reproductive tract; this subset of innate host defense peptides—including DEFB112—may play a dual role in fertility and antimicrobial defense, hinting at additional layers of extracellular matrix and immune regulation beyond cathepsin K’s activities."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "29", "end_ref": "34"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Chao Yang Li, Karl J Jepsen, Robert J Majeska, et al. 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