{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Latent transforming growth factor‐β binding protein 3 (LTBP3) is an extracellular matrix glycoprotein that plays a central role in the regulation of TGF‐β bioavailability and signaling. Through its ability to bind the latent TGF‐β complex, LTBP3 facilitates the proper secretion, deposition, and spatial targeting of TGF‐β within the matrix, thereby influencing diverse biological processes. For example, LTBP3 has been implicated in skeletal homeostasis, as genetic studies have revealed that alterations in or near the LTBP3 locus are associated with bone mineral density variation and osteoporotic fracture risk."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In osteoclasts, transcriptional regulation of LTBP3 by NFATc1 is critical for the expression of genes that drive bone resorption, linking LTBP3 to the control of osteoclast activation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": " In vivo studies using Ltbp3‐null mouse models further indicate that loss of LTBP3 perturbs TGF‐β signaling during development, leading to cranio‐facial malformations as well as defective lung septation and emphysema, which underscore its importance in proper tissue morphogenesis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": " Moreover, LTBP3 can modulate the activity of other TGF‐β superfamily members; for instance, its co‐expression with pro‐myostatin in skeletal muscle serves to sequester the inactive precursor in the extracellular matrix, thereby regulating myostatin activation and muscle growth."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " In addition, aberrant regulation of LTBP3 expression—such as that mediated by the long noncoding RNA MALAT1 in mesenchymal stem cells—can affect TGF‐β bioavailability in the tumor microenvironment, suggesting that LTBP3 may also participate in the modulation of cancer cell–stromal interactions."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " Finally, studies integrating TGF‐β/SMAD3 signaling networks and extracellular matrix maturation have identified LTBP3 as a prominent component of the high molecular weight latent TGF‐β complexes that accumulate in the matrix over time."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "9"}]}, {"type": "t", "text": " Collectively, these findings highlight a nonredundant role for LTBP3 as an ECM scaffold protein that modulates TGF‐β signaling in development, bone remodeling, and muscle regulation, and suggest that its dysregulation can contribute to diverse pathological conditions.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Emma L Duncan, Patrick Danoy, John P Kemp, et al. 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