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Purpose: Although more than 18,000,000 fractures occur each year in the US, methods to promote fracture healing still rely primarily on fracture stabilization, with use of bone anabolic agents to accelerate fracture repair limited to rare occasions when the agent can be applied to the fracture surface. Because management of broken bones could be improved if bone anabolic agents could be continuously applied to a fracture over the entire course of the healing process, we undertook to identify strategies that would allow selective concentration of bone anabolic agents on a fracture surface following systemic administration. Moreover, because hydroxyapatite is uniquely exposed on a broken bone, we searched for molecules that would bind with high affinity and specificity for hydroxyapatite. We envisioned that by conjugating such osteotropic ligands to a bone anabolic agent, we could acquire the ability to continuously stimulate fracture healing.
Results: Although bisphosphonates and tetracyclines were capable of localizing small amounts of peptidic payloads to fracture surfaces 2-fold over healthy bone, their specificities and capacities for drug delivery were significantly inferior to subsequent other ligands, and were therefore considered no further. In contrast, short oligopeptides of acidic amino acids were found to localize a peptide payload to a bone fracture 91.9 times more than the control untargeted peptide payload. Furthermore acidic oligopeptides were observed to be capable of targeting all classes of peptides, including hydrophobic, neutral, cationic, anionic, short oligopeptides, and long polypeptides. We further found that highly specific bone fracture targeting of multiple peptidic cargoes can be achieved by subcutaneous injection of the construct.
Conclusions: Using similar constructs, we anticipate that healing of bone fractures in humans that have relied on immobilization alone can be greately enhanced by continuous stimulation of bone growth using systemic administration of fracture-targeted bone anabolic agents.
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http://dx.doi.org/10.1016/j.jconrel.2020.09.047 | DOI Listing |
Cell Mol Life Sci
December 2024
Center for Mitochondrial Research and Medicine, College of Medicine Chang Gung University, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.
Imbalances in gut microbiota and their metabolites have been implicated in osteoporotic disorders. Trimethylamine-n-oxide (TMAO), a metabolite of L-carnitine produced by gut microorganisms and flavin-containing monooxygenase-3, is known to accelerate tissue metabolism and remodeling; however, its role in bone loss remained unexplored. This study investigates the relationship between gut microbiota dysbiosis, TMAO production, and osteoporosis development.
View Article and Find Full Text PDFMol Cell Endocrinol
December 2024
Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow, UP, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad- 201002, India. Electronic address:
Excessive consumption of saturated fatty acids creates a debilitating cellular environment that hinders the normal function and survival of osteoblasts, contributing to bone metabolic disorders such as osteoporosis. The FDA-approved polypeptide PTH 1-34 is a well-established therapy for post-menopausal osteoporosis, yet its protective effects in a palmitic acid (PA)-rich hyperlipidemic environment are not well understood. This study investigates the impact of PTH 1-34 on PA-induced cellular responses in osteoblasts.
View Article and Find Full Text PDFHum Cell
December 2024
Department of Integrative Bioscience and Biotechnology, Institute of Bioscience, Institute of Anticancer Medicine Development, Sejong University, Seoul, 143-747, Korea.
Human pluripotent stem cells (hPSCs) have at least three distinct states: naïve pluripotency that represents the cellular states of the pre-implantation epiblast cells, primed pluripotency that represents the cellular states of the post-implantation epiblast cells, and formative pluripotency that represents a developmental continuum between naïve and primed pluripotency. Various cell surface markers have been used to define and analyze primed and naïve hPSCs within heterogeneous populations. However, not much is known about common cell surface markers for the different pluripotent states of hPSCs.
View Article and Find Full Text PDFNeurochem Res
December 2024
Department of Spinal Surgery, Yantai Hospital of Traditional Chinese Medicine, No.39, Xingfu Road, Zhifu District, Yantai, 264000, China.
Schwann cells (SCs) are necessary for peripheral nerve regeneration due to their plasticity and trophic supply after sciatic nerve injury (SNI). However, the multiple adaptations of SCs are still poorly understood. This study explored the effects of transient axonal glycoprotein type-1 (TAG-1) on cell migration and neuropilin1 (NRP1) expression in SCs and examined the impact of TAG-1 on nerve regeneration in rats with SNI.
View Article and Find Full Text PDFConnect Tissue Res
December 2024
Graduate School of Medical and Dental Sciences, Institute of Science Tokyo, Tokyo, Japan.
Aim: We aimed to investigate whether α-ketoglutarate (AKG) can promote autophagic activity under a peri-implant condition to enhance the osseointegration of dental implant in rats with osteoporosis (OP).
Methods: Con, Model and AKG groups were established for the random allocation of thirty rats ( = 10). Their bone metabolism indicators were measured.
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