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

The BM Niche: Where Bone and Marrow Meet

Bone is the chest for BM cells and the place where the egress of stem cells, including those already committed towards some specific lineages, is orchestrated.[56] The transfer of HSPCs out of the BM to the circulation requires the integrity of bone microarchitecture, within which is contained the BM functional unit: the niche.

A niche is defined as a specialized microenvironment of the BM, specific for each cell lineage, that hosts and modulates HSPC renewal and egress into the bloodstream. Inside the niche, a complicated network of hormones, soluble mediators and surface cell receptors regulates the HSPC number, fate and location.[57] The niche is perivascular and located within the trabecular bone and is settled by osteoblastic cells, endothelial cells and perivascular MSCs that interact closely with each other.[57,58] The BM niche consists of two major elements. The first is the osteoblastic niche, where cells of the osteoblastic lineage are key modulators of HSPCs, keeping them quiescent for the purposes of maintenance and self-renewal. The second element is the vascular niche, composed of vascular sinuses, lining endothelial cells, CXCL12-abundant reticular (CAR) cells, sympathetic neurons and HSPCs. Each HSPC evolves inside a specialized and specific niche.[57] Egress of HSPCs out of the BM and into the bloodstream is known as 'mobilization' and is coupled with HSPC 'homing'. Homing is a set of complex pathways that modulate the mobilization of HSPCs towards both peripheral BM niches and peripheral tissues.[59]

The niche composition and function ultimately depends on the activity of the bone cells since most HSPCs are found in the trabecular bone, suggesting that the function of the niche (mobilization and homing) may also be regulated by factors involved in bone remodelling.[57,58,60]

A high number of osteoblasts raises the stem cell pool size and adherence in the niche, whereas an increase in osteoclasts degrades the niche and promotes the egress of HSPCs.[61]

These processes are physiologically carried by the joint effect of PTH and inflammatory cytokines. PTH plays the role of pivotal director of the niche through activation of PTH/PTHrP receptors (PPRs), leading to HSPC expansion. Following PPR activation, osteoblastic cells produce high levels of the Notch ligand, jagged-1, which elicits an increase in the number of HSPCs.[58,62,63] Furthermore, in osteoblasts PTH upregulates both granulocyte colony-stimulating factor (GCSF), which in turn regulates the expression of inflammatory cytokines (IL-6 and IL-11) and CXCL12. CXCL12 is the hinge chemokine involved in the mobilization and homing processes as its interaction with the homing receptor CXCR-4, expressed on many progenitors, is the most important pathway for retention of HSPCs within the BM as well as for their mobilization. GCSF depletes osteoblasts and reduces CXCL12 expression in both osteoblasts and CAR cells, so promoting mobilization of HSPCs into the vascular sinuses.[57,58,64]

No less relevant, within the BM niche, is the role of proinflammatory cytokines, which maintain the HSPC pool by tuning size, cell lineage, distribution and phenotype.[65] Inflammatory cytokines also affect the phenotype of BM macrophages (also called osteal macrophages): this process is known as macrophage polarization. Osteal macrophages are involved in bone repair and remodelling by regulating the crosstalk between osteoclasts and osteoblasts.[66,67]

Besides PTH, other factors involved in bone remodelling, such as FGF23/klotho, Wnt inhibitors, vitamin D, vitamin D receptor and Ca sensing receptor (CaSR), are able to influence the activity of the BM niche and the HSPC fate.[9,22,68–70] Moreover, MSCs give rise to osteoblasts, and their differentiation is stimulated by 1, 25(OH)2D. In addition to being targets of 1, 25(OH)2D, MSCs can synthesize it.[71,72] Normal CaSR expression on HSPCs is an absolute requirement for their lodging in the endosteal niche of the BM.[73]

Given these tight morphological and functional links, any pathological condition able to induce an imbalance in bone remodelling and a derangement in cell signaling may disrupt both the bone microarchitecture and the BM niche function and consequently the HSPC traffic.[74]

All these findings are new features of the complex scenario of the bone–vascular axis. In fact, HSPCs and the precursors of cardiovascular cells may also be resident in the vascular or valvular wall or be part of the uninterrupted flow of HSPCs ensuring adequate cell renewal and contributing physiologically to vascular health[75,76] (Figure 4).

Figure 4.

The fate of HSPCs out of the BM physiologically reflects the joined action of bone remodelling and inflammatory cytokines. PTH, by acting on osteoblasts both directly and indirectly (through JAG 1, IL-6 and GCSF), is pivotal director of HSPCs 'mobilization' and 'homing' into the bloodstream. Other factors involved with bone metabolism like FGF23, calcitriol, their receptors and the Ca-sensing receptor are relevant regulators of BM niche function. Their derangements in CKD, together with the resulting damage in terms of bone turnover and microarchitecture, are most likely responsible for BM niche dysfunction.

Several chronic diseases such as obesity, atherosclerosis, diabetes and CKD display a unique proinflammatory milieu that, along with a cluster of metabolic derangements and oxidative stress factors, may impair mobilization and homing, thereby inducing shortage and functional impairment of HSPCs, shifting the progenitor cell phenotype and ultimately influencing pathological processes such as atherosclerosis and vascular calcification.

Diabetes is characterized by a broad derangement of the BM niche, with an expanded pool of quiescent HSPCs as well as a reduced number of osteoblasts slightly expressing CXCL12 and unchanged CXCL12 expression in CAR cells, resulting in decreased mobilization of haematopoietic stem cells.[4] These changes are acknowledged to be driven by chronic inflammation, stimulation of innate immunity receptors, and an increase in proinflammatory osteal macrophages.[4,77,78] This novel type of diabetic complication, termed 'stem cell mobilopathy', is the pathway via which diabetes accelerates atherosclerosis; it does this by inducing a shortage of vascular regenerative cells and by shifting the differentiation of BM progenitor cells to pro-calcific.[77]

In CKD patients the uraemic inflammatory burden is enhanced by the frequent coexistence of diabetes, atherosclerosis and ageing.[34] In addition, in CKD patients, inflammation is triggered by specific pathways related to the CKD-MBD syndrome. Besides PTH, FGF23 can directly bind and activate FGFR4 and calcineurin/NFAT signaling in hepatocytes in the absence of its classic co-receptor alpha-Klotho, leading to increased expression and secretion of inflammatory cytokines (Figure 1).

The relationship between FGF23 and inflammation seems to be bidirectional since inflammation increases FGF23 transcription in osteocytes. However, whether FGF23 stimulates inflammatory cytokine expression by other target cells such as adipocytes and osteoblasts is a matter of discussion.[79] FGF23 may influence the bone microarchitecture by directly tuning bone remodelling. FGF23, through a soluble Klotho/MAPK-mediated process involving Dkk1 expression, inhibits the osteoblastic Wnt pathway, so contributing to bone loss in CKD.[69] Moreover, both human pre-osteoclasts and mature osteoclasts express FGFR1 at all stages of differentiation, and FGF23 displays biphasic effects on human osteoclasts, with inhibition of osteoclast differentiation at the early stages of maturation and stimulation of activity at later stages.[80]

CKD-related inflammation and bone mineral disorders could affect the complex balance within the BM niche, thus deranging the mobilization and homing of HSPCs and fostering the development of cell subsets expressing an osteogenic phenotype. This latter finding may represent a common thread that links bone remodelling, the BM niche and vascular calcification in chronic renal failure.

Cells with an osteogenic phenotype may originate from vascular wall-resident MSCs, transdifferentiated mature or circulating vascular smooth muscle cells, or circulating calcifying cells (CCCs).[75,81] CCCs comprise several osteogenic cell subsets that express different but interrelated phenotypes, share a common origin from BM progenitor cells, and are able to promote intimal calcification. Regardless of the type of BM progenitor cell, CCCs are defined by the expression of OC and bone alkaline phosphatase. Their pool includes circulating (mesenchymal) osteoprogenitor cells, circulating calcifying endothelial progenitor cells (EPCs) and myeloid calcifying cells (MCCs).[82] EPCs have been associated with coronary artery disease, calcific aortic stenosis, OP, diabetes and ESRD.[72,83–85] MCCs belong to the myeloid lineage (monocytes–macrophages) and have been found to be significantly increased in the presence of either cardiovascular disease or diabetes. In addition, MCC numbers are higher in diabetic versus non-diabetic patients regardless of the coexistence of cardiovascular disease, and they are also increased in the BM and atherosclerotic plaques.[86]

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