Diabetic bone fragility through advanced glycation end product-collagen axis: Mechanisms and therapy of sodium glucose cotransporter 2 inhibitors

Figure 2 Dual-pathway schematic of collagen type I crosslinking shift from “tough-ductile” to “stiff-brittle”. A: Enzymatic crosslinking pathway: The lysyl oxidase family catalyzes the oxidation of lysine/hydroxylysine residues on type I collagen, generating aldehydes that form initial divalent crosslinks, hydroxylysine and dihydroxylysinonorleucine, which gradually mature into trivalent pyridinoline crosslinks, including hydroxylysylpyridinoline and lysylpyridinoline, endowing the bone matrix with ductility and postyield toughness; B: Nonenzymatic crosslinking pathway: Hyperglycemia and oxidative stress promote the formation of reactive dicarbonyls such as methylglyoxal, which in turn induce advanced glycation end products (AGEs) to crosslink, such as pentosidine and glucosepane. These AGEs stiffen collagen fibrils and predispose the bone matrix to brittle failure; C: AGEs and their metabolic derivatives (e.g., Nepsilon-(carboxymethyl)lysine, Nepsilon-(carboxyethyl)lysine, pentosidine, methylglyoxal, and glucosepane) further suppress lysyl oxidase gene expression, thereby inhibiting enzymatic crosslink formation and contributing to a maladaptive “gain-loss” imbalance between the two pathways; D: In healthy bone, the enzymatic crosslinking-dominated “tough-ductile” model enables resilience under high load and strain. In contrast, diabetic bone, owing to AGE accumulation and impaired enzymatic crosslinking, presents a “stiff-brittle” mechanical profile characterized by early strength decline and insufficient energy absorption. LOX: Lysyl oxidase; COL1: Type I collagen; HLNL: Hydroxylysine; DHLNL: Dihydroxylysinonorleucine; HP: Hydroxylysylpyridinoline; LP: Lysylpyridinoline; LH2: Lysyl hydroxylase 2; MGO: Methylglyoxal; AGEs: Advanced glycation end products; CEL: Nepsilon-(carboxyethyl)lysine; CML: Nepsilon-(carboxymethyl)lysine.