title: Leptin receptor deficient diabetic (db/db) mice are compromised in postnatal bone regeneration.
abstract: Increased fragility fracture risk with improper healing is a frequent and severe complication of insulin resistance (IR). The mechanisms impairing bone health in IR are still not fully appreciated, which gives importance to studies on bone pathologies in animal models of diabetes. Mice deficient in leptin signaling are widely used models of IR and its comorbidities. Leptin was first recognized as a hormone, regulating appetite and energy balance; however, recent studies have expanded its role showing that leptin is a link between insulin-dependent metabolism and bone homeostasis. In the light of these findings, it is intriguing to consider the role of leptin resistance in bone regeneration. In this study, we show that obese diabetic mice lacking leptin receptor (db/db) are deficient in postnatal regenerative osteogenesis. We apply an ectopic osteogenesis and a fracture healing model, both showing that db/db mice display compromised bone acquisition and regeneration capacity. The underlying mechanisms include delayed periosteal mesenchymatic osteogenesis, premature apoptosis of the cartilage callus and impaired microvascular invasion of the healing tissue. Our study supports the use of the db/db mouse as a model of IR associated bone-healing deficits and can aid further studies of mesenchymatic cell homing and differentiation, microvascular invasion, cartilage to bone transition and callus remodeling in diabetic fracture healing.
authors.affiliation: Department of Cardiovascular Development and Repair, Spanish National Cardiovascular Research Center (Centro Nacional de Investigaciones Cardiovasculares Carlos III), Calle Melchor Fernández Almagro 3, 28029, Madrid, Spain, troszer@cnic.es.
authors.forename: Tamás
authors.initials: T
authors.lastname: Rőszer
authors.forename: Tamás
authors.initials: T
authors.lastname: Józsa
authors.forename: Eva D
authors.initials: ED
authors.lastname: Kiss-Tóth
authors.forename: Nora
authors.initials: N
authors.lastname: De Clerck
authors.forename: Lajos
authors.initials: L
authors.lastname: Balogh
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D001861:Bone Regeneration; D001842:Bone and Bones / Q000473:pathology / Q000648:ultrastructure; D002356:Cartilage / Q000473:pathology; D019902:Chondrocytes / Q000473:pathology; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000378:metabolism* / Q000473:pathology*; D005260:Female; D005264:Femoral Fractures / Q000150:complications / Q000000981:diagnostic imaging / Q000473:pathology; D017102:Fracture Healing; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D018919:Neovascularization, Physiologic; D010012:Osteogenesis; D010641:Phenotype; D011859:Radiography; D054411:Receptors, Leptin / Q000172:deficiency* / Q000378:metabolism
chemical_list: D054411:Receptors, Leptin; C515447:leptin receptor, mouse