2. Academic Validation
  3. Rescue of High Glucose Impairment of Cultured Human Osteoblasts Using Cinacalcet and Parathyroid Hormone

Rescue of High Glucose Impairment of Cultured Human Osteoblasts Using Cinacalcet and Parathyroid Hormone

  • Calcif Tissue Int. 2023 Feb 8. doi: 10.1007/s00223-023-01062-7.
V A Shahen 1,  A Schindeler 2 3,  M S Rybchyn 4,  C M Girgis 2 5 6,  B Mulholland 7 8,  R S Mason 9,  I Levinger 10 11,  T C Brennan-Speranza 12 13
Affiliations

Affiliations

  • 1 School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, 2006, Australia.
  • 2 Sydney Medical School, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, 2006, Australia.
  • 3 Bioengineering & Molecular Medicine Laboratory, The Children's Hospital at Westmead and the, Westmead Institute for Medical Research, Westmead, NSW, 2006, Australia.
  • 4 School of Chemical Engineering, University of New South Wales, Sydney, NSW, 2033, Australia.
  • 5 Department of Diabetes and Endocrinology, Westmead Hospital, Sydney, Australia.
  • 6 Department of Endocrinology, Royal North Shore Hospital, Sydney, Australia.
  • 7 Graduate School of Medicine, Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, Australia.
  • 8 Susan Wakil School of Nursing and Midwifery, Faculty of Medicine and Health, University of Sydney, Sydney, Australia.
  • 9 School of Life and Environmental Sciences, Faculty of Science, University of Sydney, Sydney, NSW, 2006, Australia.
  • 10 Institute for Health and Sport (IHES), Victoria University, Melbourne, VIC, Australia.
  • 11 Australian Institute for Musculoskeletal Science (AIMSS), University of Melbourne and Western Health, St Albans, VIC, Australia.
  • 12 School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, 2006, Australia. [email protected].
  • 13 School of Public Health, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, 2006, Australia. [email protected].
PMID: 36754901 DOI: 10.1007/s00223-023-01062-7
Abstract

Patients with type 2 diabetes mellitus (T2DM) experience a higher risk of fractures despite paradoxically exhibiting normal to high bone mineral density (BMD). This has drawn into question the applicability to T2DM of conventional fracture reduction treatments that aim to retain BMD. In a primary human osteoblast culture system, high glucose levels (25 mM) impaired cell proliferation and matrix mineralization compared to physiological glucose levels (5 mM). Treatment with parathyroid hormone (PTH, 10 nM), a bone anabolic agent, and cinacalcet (CN, 1 µM), a calcimimetic able to target the Ca2+-sensing receptor (CaSR), were tested for their effects on proliferation and differentiation. Strikingly, CN+PTH co-treatment was shown to promote cell growth and matrix mineralization under both physiological and high glucose conditions. CN+PTH reduced Apoptosis by 0.9-fold/0.4-fold as measured by Caspase-3 activity assay, increased Alkaline Phosphatase (ALP) expression by 1.5-fold/twofold, increased the ratio of nuclear factor κ-B ligand (RANKL) to Osteoprotegerin (OPG) by 2.1-fold/1.6-fold, and increased CaSR expression by 1.7-fold/4.6-fold (physiological glucose/high glucose). Collectively, these findings indicate a potential for CN+PTH combination therapy as a method to ameliorate the negative impact of chronic high blood glucose on bone remodeling.

Keywords

Cinacalcet; Diabetes; Osteoblasts; PTH; Parathyroid hormone.

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