{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Low‐density lipoprotein receptor–related protein 5 (LRP5) is a critical co‐receptor in the canonical Wnt/β–catenin signaling cascade that regulates skeletal development and homeostasis. In bone, LRP5 mediates osteoblast proliferation, differentiation, and survival, thereby influencing bone mass accrual. Gain–of–function mutations in LRP5 result in increased bone formation and a high bone mass phenotype, as demonstrated by human genetic studies and corresponding transgenic mouse models."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": " Conversely, loss–of–function mutations or targeted disruption of LRP5 lead to deficient osteoblast activity, impaired mechanotransduction, and low bone mass disorders such as osteoporosis–pseudoglioma syndrome."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "4", "end_ref": "6"}]}, {"type": "t", "text": " LRP5 function is modulated by natural antagonists such as Dickkopf–1 and sclerostin which bind to or alter the cell surface availability of LRP5, thereby fine–tuning Wnt signaling and bone remodeling."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " In addition, LRP5 has been shown to regulate bone formation indirectly through control of gut–derived serotonin synthesis, establishing a link between intestinal homeostasis and skeletal anabolism."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": " Furthermore, studies in mesenchymal progenitors and osteoblastic cells highlight that LRP5–mediated Wnt signaling is essential for the induction of osteoblast differentiation and extracellular matrix mineralization"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": ", and mutations in LRP5 are also implicated in various sclerosing bone disorders."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": " Finally, experiments employing osteocyte–specific expression of mutant LRP5 underscore the local, cell–autonomous role of this receptor in maintaining bone mass and quality."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": " Collectively, these findings affirm that LRP5 is a pivotal mediator of bone anabolic processes and a promising therapeutic target for the treatment of metabolic bone diseases.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Lynn M Boyden, Junhao Mao, Joseph Belsky, et al. 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