Docosahexaenoic acid improves altered mineralization proteins, the decreased quality of hydroxyapatite crystals and suppresses oxidative stress induced by high glucose

Abstract

Patients with type 2 diabetes mellitus (DM2) experience an increased risk of fractures and a variety of bone pathologies, such as osteoporosis. The suggested mechanisms of increased fracture risk in DM2 include chronic hyperglycaemia, which provokes oxidative stress, alters bone matrix, and decreases the quality of hydroxyapatite crystals. Docosahexaenoic acid (DHA), an omega-3 fatty acid, can increase bone formation, reduce bone loss, and it possesses antioxidant/anti-inflammatory properties. The present study aimed to determine the effect of DHA on altered osteoblast mineralisation and increased reactive oxygen species (ROS) induced by high glucose concentrations. A human osteoblast cell line was treated with 5.5 mM glucose (NG) or 24 mM glucose (HG), alone or in combination with 10 or 20 µM DHA. The collagen type 1 (Col1) scaffold, the expression of osteocalcin (OCN) and bone sialoprotein type-II (BSP-II), the alkaline phosphatase (ALP) specific activity, the mineral quality, the production of ROS and the mRNA expression of nuclear factor erythroid 2-related factor-2 (NRF2) were analysed. Osteoblasts cultured in HG and treated with either DHA concentration displayed an improved distribution of the Col1 scaffold, increased OCN and BSP-II expression, increased NRF2 mRNA, decreased ALP activity, carbonate substitution and reduced ROS production compared with osteoblasts cultured in HG alone. DHA counteracts the adverse effects of HG on bone mineral matrix quality and reduces oxidative stress, possibly by increasing the expression of NRF2.

The extracellular matrix of human bone marrow adipocytes and glucose concentration differentially alter mineralization quality without impairing osteoblastogenesis

“…In the absence of ECM and compared to normoglycemic condition, the mineralized matrix generated in the HG concentration displayed an increase in the mineral-to-matrix ratio and the type-B carbonate substitution level. The latter alteration (corresponding to a substitution of a phosphate by a carbonate group) is in agreement with the reduced calcium to phosphorus ratio already mentioned ( García-Hernández et al, 2012 ) and has also been recently reported using a human osteoblast cell line ( Cifuentes-Mendiola et al, 2022 ). Increased mineralization of the organic matrix is a feature of the cortical region of long bones in most rodent models of T2D ( Creecy et al, 2016 ; Hammond et al, 2014 ; Hunt et al, 2018 ).…”

“…In contrast, we ( Fig. 5 D) and others ( Cifuentes-Mendiola et al, 2022 ) show that HG exposure alone results in a higher carbonate substitution level; which indicates that other mechanisms are involved to modulate such change within the mineral. It should be noted that continuous insulin administration decreases the type B carbonate substitution in the bones of T2D rats independently of the restoration of glycemia, suggesting that lack of insulin effect may also be implicated in such defects ( Shi et al, 2021 ).…”

Causal link between docosahexaenoic acid and osteoporosis: A 2-sample Mendelian randomization study

“…There have been numerous similar studies conducted on this topic. [21] However, the topic of DHA's effects on bones is controversial despite research supporting its positive effects.…”