High-density lipoprotein (HDL) metabolism and bone mass

Abstract

It is well appreciated that high-density lipoprotein (HDL) and bone physiology and pathology are tightly linked. Studies, primarily in mouse models, have shown that dysfunctional and/or disturbed HDL can affect bone mass through many different ways. Specifically, reduced HDL levels have been associated with the development of an inflammatory microenvironment that affects the differentiation and function of osteoblasts. In addition, perturbation in metabolic pathways of HDL favors adipoblastic differentiation and restrains osteoblastic differentiation through, among others, the modification of specific bone-related chemokines and signaling cascades. Increased bone marrow adiposity also deteriorates bone osteoblastic function and thus bone synthesis, leading to reduced bone mass. In this review, we present the current knowledge and the future directions with regard to the HDL-bone mass connection. Unraveling the molecular phenomena that underline this connection will promote the deeper understanding of the pathophysiology of bone-related pathologies, such as osteoporosis or bone metastasis, and pave the way toward the development of novel and more effective therapies against these conditions.

Keywords: adipose tissue; apolipoprotein; bone formation and resorption; cholesterol; skeletal biology.

Figure 1

Diagram depicting the growth factors, cytokines and receptors that are involved in the “coupling” between osteoblasts and osteoclasts and the regulation of osteoclast maturation and bone resorption. These phenomena that take place in the bone marrow, are described in detail in the text. It should be noted that mature osteoclasts should adhere tightly to bone surfaces (mainly through ανβ3 intern adhesions) in order to accomplish bone resorption. Moreover, note that the activated osteoblasts are large, cuboidal cells, with hefty nucleus; on the contrary, inactive bone lining cells are spindle shaped, with small elongated nucleus. Under specific stimuli, bone lining cells become metabolically active osteoblasts, regaining their bone-producing capacity. Abbreviations: BLC: bone lining cells, CSF1: colony stimulation factor-1, HSC: hematopoietic stem cells, IL: interleukin, MMP: matrix metalloproteases, OCL: osteoclasts, OBL: osteoblasts, OCT: osteocyte, OPG: osteoprotegerin, RANK: receptor activator for nuclear factor k B, RANKL: RANK-Ligand, SC: stromal cells.

Figure 2

This diagram shows the molecular mechanisms that underline the effect of impaired and/or dysfunctional HDL on bone mass. The red arrows represent the “positive” effects, the blue arrows represent the “negative” effects and the green arrows are indicative of “no” or “undefined” effect. Abbreviations: ANXA2: Annexin-2, BM-ADC: bone marrow adipocytes, CLCX12: CXC chemokine ligand 12, Coll: collagen, IL: interleukin, MCP: macrophages, MSC: mesenchymal stem cells, OC: osteocalcin, OCL: osteoclast, OBL: osteoblast,ON: osteonectin,OPN: osteopontin, RANK: receptor activator for nuclear factor k B, RANKL: RANK Ligand, TNFα: tumor necrosis factor alpha.

Figure 3

Diagram depicting the molecular changes observed in the ApoA-1 knock out mice (B) in comparison to their wild type counterparts (A). All the molecular alterations are described in detail in the text. Note that the increased or decreased expression levels are represented by larger or smaller boxes. For example in the ApoA-1 deficient mice, the expression of CXCL12 is significantly decreased (X0.3), while the expression levels of its' CXCL12 receptor CXCR4 is greatly elevated (X3). Abbreviations: APOA1: Apolipoprotein A-1, CLCX12: CXC chemokine ligand 12, CXCR4: CXC Receptor 4, LBL: lipoblast, MSC: mesenchymal stem cells, OBL: osteoblast, WT: wild type.