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


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

In This Article

Bone, Inter-organ Communications and CKD

Until recently, bone was perceived as the repository of ions—mainly calcium (Ca) and phosphate (P)—whose movement into and out of bone was regulated by parathyroid hormone (PTH) and active vitamin D through actions on osteoblasts and osteoclasts. This view changed with the discovery that osteocytes, previously thought to be inactive, in fact orchestrate osteoblast and osteoclast activity, including the synthesis of proteins with hormonal or hormone-like properties. Accordingly, bone is now recognized as an endocrine organ,[5] and at least three bone proteins have been claimed to have potential systemic effects: osteocalcin (OC), fibroblast growth factor 23 (FGF23), and sclerostin (Sost).

OC, the most abundant non-collagenous bone protein, is produced by osteoblasts during bone synthesis; however, during osteoclastic resorption OC is transformed into undercarboxylated OC (UcOC), which is freed into blood. By binding to a G protein-coupled receptor in beta pancreatic cells, circulating UcOC affects insulin sensitivity and muscle energy metabolism. Accordingly, OC is regarded as a biochemical mediator of inter-organ communication between bone and muscle energy.[6]

FGF23, mainly produced by osteocytes, is a completely new player in the field of so-called CKD–mineral and bone disorders (CKD-MBD).[7] By binding to FGF receptors, and in the presence of a co-receptor, alpha-Klotho, which is mainly produced in the kidney,[8] circulating FGF23 regulates P handling and vitamin D synthesis in renal tubular cells. The FGF23/Klotho system is essential for P and vitamin D metabolism and represents the biochemical substrate of the inter-organ communication between bone and kidney, useful for better classification of some rare diseases.[9] Notably, in end-stage renal disease (ESRD) circulating FGF23 levels increase dramatically as an extreme bone response to the burden of P load and altered catabolism. This strong interaction between P and FGF23 has widened the spectrum of P toxicity to include, besides secondary hyperparathyroidism, cardiovascular disease (similarly to cholesterol).[10,11] In fact, higher quartiles of FGF23 have been associated with poor cardiovascular outcomes in renal[12–14] and non-renal patients,[15] probably due to a direct, receptor-mediated effect of FGF23 on myocardiocytes that is capable of inducing left ventricular hypertrophy and myocardial fibrosis independently of the FGF co-receptor Klotho.[16] Further, Ca deficiency reduces circulating levels of FGF23, thus decreasing the FGF23-mediated inhibition of 1, 25(OH)2D3, which would exacerbate hypocalcaemia.[17] FGF23 synthesis in bone is regulated by a number of bone proteins with either inhibitory or stimulatory effects.[18] Therefore, FGF23 can also be regarded as an inter-organ communication factor between bone and the heart.

Sost, produced by osteocytes, is a powerful inhibitor of the canonical Wnt (wingless-type mouse mammary tumour virus integration site) pathway and, as such, is both an inhibitor of osteoblasts and osteocytes and a promoter of osteoclast activity.[19] Indeed, human inactivating mutations of the Sost gene are associated with sclerosteosis,[20] while absence of mechanical load (e.g. due to inactivity or absence of gravity) increases Sost expression in bone, promoting bone resorption and osteoporosis (OP).[21] Also, Sost stimulates FGF23 synthesis, thus exerting indirect effects on mineral metabolism.[22] Importantly, extraskeletal roles are envisaged, since Sost mRNA expression has been described,[23] although not consistently,[24] in calcified aortic valves of haemodialysis patients, while higher circulating levels are invariably associated with aortic valve calcification.[23,24] Vessel wall media layer calcification, commonly identified as arteriosclerosis, is a typical finding of ageing, diabetes and CKD whose pathogenesis is now regarded as a cell-mediated active process involving osteoblast-like cells derived from vascular smooth muscle cells. Therefore, a modulator of osteoblast activity like Sost could well be involved. Hypothetically, increased tissue levels of Sost might reflect local inhibition of the osteoblast-like cell-mediated process of calcification or high circulating levels of Sost might be a marker of low bone turnover (which in turn would favour vascular calcifications). Thus, the extraskeletal effects of Sost have potential clinical implications for cardiovascular diseases and represent a new player in the bone–vascular axis.

Besides UcOC, FGF23 and Sost, which can be regarded as the principal mediators of the systemic 'CKD-MBD syndrome',[25] other non-collagenous bone proteins like bone alkaline phosphatase,[26] the Small Integrin-Binding Ligand, N-linked Glycoprotein (SIBLING) proteins,[18] DKK-1 and activin A[27] are under investigation to elucidate links between bone disease, derangements of divalent ion metabolism, and the burden of mortality and morbidity (in particular cardiovascular) carried by CKD-MBD.[25]

In summary, bone is no longer to be viewed as a lifeless framework for muscle action; rather, it is a sophisticated organ functionally connected with muscle energy metabolism, with the kidney and with the cardiovascular system (Figure 1). CKD deeply disturbs bone physiology (as reflected by changes in circulating biomarkers), impairs its mechanical competence (as reflected by an increased fracture rate) and contributes to the complex endocrinopathy now associated with worse cardiovascular outcomes. For this reason, there is growing awareness that in renal patients it is important to recognize the specific types of renal osteodystrophy (ROD) through a bone biopsy, which is not routinely performed although it is minimally invasive and is considered the diagnostic gold standard.[28]

Figure 1.

UcOC, FGF23 and Sost are the principal mediators of the systemic metabolic effects of bone. UcOC increases insulin response of target organs and is involved with energy metabolism. Klotho-dependent receptor-mediated effects of FGF23 mainly affect mineral metabolism, while Klotho-independent effects on heart and liver produce systemic effects. Sost, a major regulator of bone cells activity, may have a role in vascular calcifications. Mineral and bone disorders resulting from CKD are expected to influence these physiologic links.