Abstract
ABSTRACTType 2 diabetes mellitus (T2DM) is a multisystemic disease that afflicts more than 415 million people globally—the incidence and prevalence of T2DM continues to rise. It is well‐known that T2DM has detrimental effects on bone quality that increase skeletal fragility, which predisposes subjects to an increased risk of fracture and fracture healing that results in non‐ or malunion. Diabetics have been found to have perturbations in metabolism, hormone production, and calcium homeostasis—particularly PTH expression—that contribute to the increased risk of fracture and decreased fracture healing. Given the perturbations in PTH expression and the establishment of hPTH (1–34) for use in age‐related osteoporosis, it was determined logical to attempt to ameliorate the bone phenotype found in T2DM using hPTH (1–34). Therefore, the present study had two aims: (i) to establish a suitable murine model of the skeletal fragility present in T2DM because no current consensus model exists; and (ii) to determine the effects of hPTH (1–34) on bone fractures in T2DM. The results of the present study suggest that the polygenic mouse of T2DM, TALLYHO/JngJ, most accurately recapitulates the diabetic osteoporotic phenotype seen in humans and that the intermittent systemic administration of hPTH (1–34) increases fracture healing in T2DM murine models by increasing the proliferation of mesenchymal stem cells. © 2020 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.
Highlights
P TH, an 84-amino acid peptide released by the parathyroid glands, is an important calcium-regulating hormone that aids in regulating bone remodeling
Hyperglycemic states have been shown to cause an increase in urinary calcium loss, resulting in a negative calcium balance that may contribute to the increased rate of bone fractures in diabetic patients.[7]. Perhaps more significantly, the persistent inflammatory state seen with chronic hyperglycemia increases chondrocyte and osteoblast apoptosis, while simultaneously encouraging osteoclast survival, tipping the scales of bone remodeling in favor of bone loss.[16] inflammatory markers, including TNFα, inhibit angiogenesis, a vital component of fracture healing and bone health.[17]. This state of calcium depletion, remodeling inequality, and angiogenic insufficiency may contribute both to the increased fracture risk and the delayed fracture healing seen in diabetic populations
The data from the present study suggest that the monogenic murine model db/db is the most accurate representation of human diabetic osteoporosis and that the intermittent administration of hPTH [1–34] may improve fracture healing capacity in human patients with type 2 diabetes mellitus (T2DM) as evidenced by this effect in the chosen murine models
Summary
P TH, an 84-amino acid peptide released by the parathyroid glands, is an important calcium-regulating hormone that aids in regulating bone remodeling. Multiple studies have shown that patients with type 2 diabetes mellitus (T2DM) are more likely to suffer osteoporotic fractures than nondiabetics.[7–9]. Such fractures are a debilitating complication of diabetes that impairs quality of life in millions of people globally. Hyperglycemic states have been shown to cause an increase in urinary calcium loss, resulting in a negative calcium balance that may contribute to the increased rate of bone fractures in diabetic patients.[7]. Inflammatory markers, including TNFα, inhibit angiogenesis, a vital component of fracture healing and bone health.[17] This state of calcium depletion, remodeling inequality, and angiogenic insufficiency may contribute both to the increased fracture risk and the delayed fracture healing seen in diabetic populations
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