Bone, Inflammation and the Bone Marrow Niche in Chronic Kidney Disease

What Do We Know?

Sandro Mazzaferro; Giuseppe Cianciolo; Antonio De Pascalis; Chiara Guglielmo; Pablo A. Urena Torres; Jordi Bover; Lida Tartaglione; Marzia Pasquali; Gaetano La Manna

Disclosures

Nephrol Dial Transplant. 2018;33(12):2092-2100. 

In This Article

Abstract and Introduction

Abstract

Recent improvements in our understanding of physiology have altered the way in which bone is perceived: no longer is it considered as simply the repository of divalent ions, but rather as a sophisticated endocrine organ with potential extraskeletal effects. Indeed, a number of pathologic conditions involving bone in different ways can now be reconsidered from a bone-centred perspective. For example, in metabolic bone diseases like osteoporosis (OP) and renal osteodystrophy (ROD), the association with a worse cardiovascular outcome can be tentatively explained by the possible derangements of three recently discovered bone hormones (osteocalcin, fibroblast growth factor 23 and sclerostin) and a bone-specific enzyme (alkaline phosphatase). Further, in recent years the close link between bone and inflammation has been better appreciated and a wide range of chronic inflammatory states (from rheumatoid arthritis to ageing) are being explored to discover the biochemical changes that ultimately lead to bone loss and OP. Also, it has been acknowledged that the concept of the bone–vascular axis may explain, for example, the relationship between bone metabolism and vessel wall diseases like atherosclerosis and arteriosclerosis, with potential involvement of a number of cytokines and metabolic pathways. A very important discovery in bone physiology is the bone marrow (BM) niche, the functional unit where stem cells interact, exchanging signals that impact on their fate as bone-forming cells or immune-competent haematopoietic elements. This new element of bone physiology has been recognized to be dysfunctional in diabetes (so-called diabetic mobilopathy), with possible clinical implications. In our opinion, ROD, the metabolic bone disease of renal patients, will in the future probably be identified as a cause of BM niche dysfunction. An integrated view of bone, which includes the BM niche, now seems necessary in order to understand the complex clinical entity of chronic kidney disease–mineral and bone disorders and its cardiovascular burden. Bone is thus becoming a recurrently considered paradigm for different inter-organ communications that needs to be considered in patients with complex diseases.

Introduction

The recognition in recent years of the embryonic origin of bone cells (osteoclasts from haematopoietic stem/progenitor cells or HSPCs, and osteoblasts from mesenchymal stem cells or MSCs) and of the hormone-like properties of a number of 'non-collagenous bone proteins' confers on bone the potential for systemic extraskeletal effects.[1] In addition, the clinical effects of chronic inflammation in various systemic diseases has increasingly been recognized. Specifically, the mild chronic increase in blood and tissues of an ever-growing number of cytokines is associated with worse clinical outcomes.[2] Another recent discovery is the osteoblastic niche, the functional unit where stem cells, precursors of both haematopoietic and bone cell lineages (respectively HSPCs and MSCs), share a common environment. In this niche, these cells exchange signals that modify their fate in terms of differentiation towards immune-competent haematopoietic elements (among which osteoclasts are now included) and bone-forming cells (i.e. osteoblasts and osteocytes). There is evidence that HSPCs and MSCs share functional integrations of potential clinical relevance.[3] The aim of this review is to highlight the emerging potential links between bone, chronic inflammation and the bone marrow (BM) niche, in particular in chronic kidney disease (CKD) patients. These patients are special because they suffer a specific type of metabolic bone disease and low-grade chronic inflammation that can affect, in still underappreciated ways, the function of the osteoblastic niche; dysfunction of the latter has recently been recognized for the first time in diabetes.[4]

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