Apolipoprotein A-1 regulates osteoblast and lipoblast precursor cells in mice

Abstract

Imbalances in lipid metabolism affect bone homeostasis, altering bone mass and quality. A link between bone mass and high-density lipoprotein (HDL) has been proposed. Indeed, it has been recently shown that absence of the HDL receptor scavenger receptor class B type I (SR-B1) causes dense bone mediated by increased adrenocorticotropic hormone (ACTH). In the present study we aimed at further expanding the current knowledge as regards the fascinating bone-HDL connection studying bone turnover in apoA-1-deficient mice. Interestingly, we found that bone mass was greatly reduced in the apoA-1-deficient mice compared with their wild-type counterparts. More specifically, static and dynamic histomorphometry showed that the reduced bone mass in apoA-1 − / − mice reflect decreased bone formation. Biochemical composition and biomechanical properties of ApoA-1 − / − femora were significantly impaired. Mesenchymal stem cell (MSC) differentiation from the apoA-1 − / − mice showed reduced osteoblasts, and increased adipocytes, relative to wild type, in identical differentiation conditions. This suggests a shift in MSC subtypes toward adipocyte precursors, a result that is in line with our finding of increased bone marrow adiposity in apoA-1 − / − mouse femora. Notably, osteoclast differentiation in vitro and osteoclast surface in vivo were unaffected in the knock-out mice. In whole bone marrow, PPARγ was greatly increased, consistent with increased adipocytes and committed precursors. Further, in the apoA-1 − / − mice marrow, CXCL12 and ANXA2 levels were significantly decreased, whereas CXCR4 were increased, consistent with reduced signaling in a pathway that supports MSC homing and osteoblast generation. In keeping, in the apoA-1 − / − animals the osteoblast-related factors Runx2, osterix, and Col1a1 were also decreased. The apoA-1 − / − phenotype also included augmented CEPBa levels, suggesting complex changes in growth and differentiation that deserve further investigation. We conclude that the apoA-1 deficiency generates changes in the bone cell precursor population that increase adipoblast, and decrease osteoblast production resulting in reduced bone mass and impaired bone quality in mice.Laboratory Investigation (2016) 96, 763-772; doi:10.1038/labinvest.2016 published online 18 April 2016 Osteoporosis is characterized by low bone mass and microarchitectural deterioration of bone, resulting in bone fragility and fracture susceptibility. 1,2 It is a major public health problem worldwide; indeed, in the United States, more than 44 million people have osteoporosis or low bone mass. 3 The pathogenesis of osteoporosis is multifactorial. Age, sex, body size, metabolic factors, and genetic susceptibility are contributory factors. Interestingly, several studies have shown that there are strong links between bone, fat metabolism, and systemic energy metabolism, and that perturbations in lipid regulatory pathways may trigger both local and systemic phenomena that ultimately affect osteoblast and/or osteoclast function, resulting...

Absence of Dipeptidyl Peptidase 3 Increases Oxidative Stress and Causes Bone Loss

“…Frozen samples of lumbar vertebrae were cryosectioned, exploiting the CryoJane® Tape‐Transfer system and tungsten blades (Leica Biosystems, Wetzlar, Germany). Mineralized surface and interlabel distance were evaluated by measuring calcein labels in the cancellous bone using the grid intersect method, and interlabel distance using minimum pixel interval at high power, as reported . Bone formation parameters were expressed as bone formation rate (BFR) and mineral surface over bone surface (MS/BS).…”

High-density lipoprotein (HDL) metabolism and bone mass

“…2001). We have very recently reported that APOA1 deficiency greatly disturbs the ANXA2-CLCX12-CXCR4 connection, providing a plausible mechanistic explanation for the impaired osteoblastic function observed in the ApoA1 KO mice (Blair et al 2016). It should also be borne in mind that the CLCX12-CXCR4 axis is also crucial for the regulation of osteoblastic bone marrow niche that participates in an array of processes, including hematopoietic stem cell (HSC) homing and mobilization and bone metastasis (Greenbaum et al 2013, Kfury & Scadden 2015).…”

“…Through a series of in vitro and molecular experiments on mesenchymal stem cells, osteoblasts and osteoclasts isolated and cultured from femora of the two mouse groups we uncovered that the osteoblast-related factors and signaling axes, RUNX2, osterix, COLLa1, RANKL, were significantly impaired in the ApoA1 KO as compared to the wild type mice. On the contrary, genes that regulate osteoclastic differentiation and function namely TRAP ( Acp5 ), cathepsin K ( Ctsk ) and RANK ( Tnfrsf11a ), were unaffected (Blair et al 2016). These interesting findings indicate that the reduced bone mass observed in the ApoA1 KO mice, is attributed primarily to suppressed osteoblastic bone synthesis and not to increased osteoclastic bone degradation.…”

“…Recently, we identified a novel role of HDL in the pathogenesis of degenerative and metabolic bone diseases using experimental mouse models (Triantaphyllidou et al . 2013, Blair et al . 2016), suggesting that low and dysfunctional HDL may contribute to an increased prevalence of these diseases by influencing molecular processes associated with bone synthesis and catabolism.…”

Osteoblast Differentiation and Bone Matrix FormationIn VivoandIn Vitro

“…However, in vivo, fatty acids are a key source for bone synthesis 12 ; elimination of the major HDL component causes severe osteoporosis. 13 Osteoblasts that are not synthesizing bone are low-columnar cells, but still form a continuous membrane (Fig. 1A).…”