We searched Embase and Medline, using “bone” and “skeleton” as obligate terms, with the following MESH terms or abstract words in all combinations of a minimum of two: “cardiovascular”, “vascular”, “glucose”, “factor”, “heart”, “cardiac”, and “metabolism”. We assessed the abstracts of the retrieved results and conditionally selected papers based on three criteria. First, the paper had to address a mainly bone-derived circulating factor; second, the regulation of that factor had to be probably
ReviewBone: a new endocrine organ at the heart of chronic kidney disease and mineral and bone disorders
Introduction
For decades, it has been acknowledged that bone is affected by chronic kidney disease (CKD). The clinical findings of bone deformations and increased incidence of bone pain and fractures, originally named Von Recklinghausen disease (after a German pathologist who described it in 1892) and now known as osteitis fibrosa cystica, led to early recognition of CKD-induced bone disease, referred to as renal osteodystrophy.1 The traditionally described cause of this disorder was secondary hyperparathyroidism, driven by phosphate retention and a progressive lack of active vitamin D, leading to hypocalcaemia.2 This conceptual framework was additionally based on pioneering findings from bone biopsy of patients with advanced CKD, which showed grossly abnormal bone architecture, comprising primarily hyperdynamic (ie, high-turnover) bone disease, the histological hallmark of hyperparathyroidism.3 The skeleton was therefore thought to be merely one of the tissues passively affected by the metabolic consequences of CKD.
This perception of bone involvement in CKD has now substantially changed after the description of two important epidemiological findings. The first was the severely increased risk of cardiovascular disease associated with CKD.4 The second finding was the consistent association between any type of bone disease at any stage of CKD and cardiovascular morbidity.5, 6 The inference from these new insights was that cardiovascular disease in CKD might be mediated or modified by bone disease. Importantly, however, this suggestion is based on epidemiological association only, and no studies have prospectively tested this hypothesis. Because the skeleton is the most important reservoir for several minerals (including calcium, phosphate, and magnesium), disturbed skeletal handling and homoeostasis of these minerals have been thought to be the link between diseased bone and cardiovascular disease, especially cardiovascular calcification. Indeed, evidence exists of a decreased so-called buffer capacity for peak loads of phosphate and calcium in cases of low bone turnover or adynamic bone disease, which could favour the deposition of these minerals in many soft tissues, particularly the arterial wall and cardiac valves.7 Conversely, increased release of these ions from bone in the setting of secondary hyperparathyroidism could also have the same harmful effects, although the quantitative effects of these mechanisms are unclear. Moreover, emerging insights have suggested that hypercalcaemia and hyperphosphataemia in conjunction can induce a phenotypic change of vascular smooth-muscle cells into bone-forming cells, genotypically strikingly resembling osteoblasts.8 This frequent coexistence of bone, mineral, and cardiovascular disorders (mineral bone disorders [MBD]), in the setting of CKD, gives rise to the now widely accepted notion of CKD-MBD as a specific entity.9
New data about the role of bone in CKD on fundamental biological pathways, (eg, mineral homoeostasis, energy and glucose metabolism, and CKD-related pathology of the cardiovascular system) have been reported, and seem to suggest a further conceptual shift, pointing to the skeleton as an active inducer of pathology as a deregulated endocrine gland in kidney disease. In this Review, we describe recent research that either substantiates or refutes this new understanding of bone in CKD.
Our search of the scientific literature suggested a small number of hormones or circulating factors that met our prespecified criteria. We identified FGF23, the Wnt inhibitors sclerostin and DKK1, and osteocalcin as factors that are mainly bone derived and potentially have distant effects. Although less obviously bone derived, the bone morphogenic proteins BMP2 and BMP7 originate at least partly from this tissue and have clear distant effects, and are probably relevant in CKD.
Section snippets
FGF23
Arguably the first, but certainly the most prominent, bone-derived factor that is clearly abnormally elevated in CKD is FGF23. Although the kidney, the liver, and coronary arteries have been suggested as sources of this factor,10, 11 overwhelming data point to bone (particularly the osteocyte) as the main production site. A unique feature of FGF23 is its low affinity for heparan sulphate (a proteoglycan found on cell surfaces or extracellular matrix), enabling it to escape from capture in bone.
Sclerostin and DKK1: Wnt inhibitors and their effects
Wnt inhibitors are secreted factors that interact with Wnt receptors or Wnt ligands and attenuate Wnt signalling activity (panel). In this Review we focus on sclerostin and DKK1. Both proteins are soluble Wnt inhibitors,48 have already undergone some experimental and clinical investigations about their role in CKD-MBD, and can be measured in human blood with use of ELISA techniques. However, when blood sclerostin measurements in CKD cohorts are compared, substantial discrepancies between assays
Osteocalcin
Osteocalcin, also known as bone gla protein, is a 6 kD calcium-binding bone-matrix protein produced by osteoblasts, and is one of the most abundant non-collagen proteins in bone. It is regulated by the two major mineral and bone-controlling hormones, vitamin D and parathyroid hormone. Osteocalcin expression by the BGLAP gene and production are directly stimulated by vitamin D through a vitamin-D-responsive element located in the promoter region of BGLAP. Parathyroid hormone also stimulates
Bone morphogenetic proteins
The capacity of bone extracts to induce ectopic bone formation has been recognised since 1965.89 However, the first bone morphogenetic protein was isolated only two decades later and named osteogenin.90 The number of bone morphogenetic proteins has since increased substantially,91 and these proteins are characterised by both the presence of a conserved C-term domain with seven cysteine residues, and by the capacity to induce several biological functions in several species.92 Bone morphogenetic
Discussion
In this Review we have summarised several new insights that point to a putative active role of skeletal tissue as an endocrine regulator of energy metabolism and mineral homoeostasis in addition to the induction and propagation of cardiovascular disease. The conceptual framework that connects bone disease to systemic pathological changes might accordingly evolve, from bone as a mere target of uraemia, through to a diseased tissue unable to handle fluctuations in phosphorus and calcium
Search strategy and selection criteria
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