Updates in the chronic kidney disease-mineral bone disorder show the role of osteocytic proteins, a potential mechanism of the bone—Vascular paradox, a therapeutic target, and a biomarker

Abstract

The chronic kidney disease-mineral bone disorder (CKD-MBD) is a complex multi-component syndrome occurring during kidney disease and its progression. Here, we update progress in the components of the syndrome, and synthesize recent investigations, which suggest a potential mechanism of the bone-vascular paradox. The discovery that calcified arteries in chronic kidney disease inhibit bone remodeling lead to the identification of factors produced by the vasculature that inhibit the skeleton, thus providing a potential explanation for the bone-vascular paradox. Among the factors produced by calcifying arteries, sclerostin secretion is especially enlightening. Sclerostin is a potent inhibitor of bone remodeling and an osteocyte specific protein. Its production by the vasculature in chronic kidney disease identifies the key role of vascular cell osteoblastic/osteocytic transdifferentiation in vascular calcification and renal osteodystrophy. Subsequent studies showing that inhibition of sclerostin activity by a monoclonal antibody improved bone remodeling as expected, but stimulated vascular calcification, demonstrate that vascular sclerostin functions to brake the Wnt stimulation of the calcification milieu. Thus, the target of therapy in the chronic kidney disease-mineral bone disorder is not inhibition of sclerostin function, which would intensify vascular calcification. Rather, decreasing sclerostin production by decreasing the vascular osteoblastic/osteocytic transdifferentiation is the goal. This might decrease vascular calcification, decrease vascular stiffness, decrease cardiac hypertrophy, decrease sclerostin production, reduce serum sclerostin and improve skeletal remodeling. Thus, the therapeutic target of the chronic kidney disease-mineral bone disorder may be vascular osteoblastic transdifferentiation, and sclerostin levels may be a useful biomarker for the diagnosis of the chronic kidney disease-mineral bone disorder and the progress of its therapy.

Analysis of factors influencing vascular calcification in peritoneal dialysis patients and their impact on long-term prognosis

“…Under normal conditions, Sclerostin regulates bone metabolism by inhibiting the process of bone formation. As an inhibitor of the Wnt signaling pathway, it suppresses the differentiation of osteoprogenitor cells into osteoblasts, thereby inhibiting the formation of new bone [ 17 ]. However, in chronic kidney disease, the expression levels of Sclerostin are often elevated, particularly during or after CKD stage III [ 18 ].…”

Chronic Kidney Disease in Patients with Hip Fracture: Prevalence and Outcomes

“…In disease states, abnormalities in any of these systems can initiate and perpetuate structural and functional dysfunction in other organs. Not surprisingly, renal impairment, abnormalities in mineral-bone metabolism, numerous diseases encompassing T2DM, CAD, hypertension, heart failure, anaemia, dementia, COPD, etc., activate each other (via the autocrine, paracrine and nervous systems), creating metabolic dysregulation and vicious cycles of damage [11,27,78,79], leading to multimorbidity (i.e., renal osteodystrophy [80], cardiorenal syndrome [81], brainkidney axis/cross-talk [82][83][84][85][86][87]; CKD-COPD interaction [78,88]) which is strongly associated with falls and fractures (Figure 2). Clearly, in the elderly multiple chronic diseases, falls and fractures are competing events that cluster, and CKD is a risk factor for abovementioned conditions, death, and other adverse outcomes.…”

Pathogenesis and Mechanism of Uremic Vascular Calcification

“…Vascular intimal calcification is often localized and is associated with atherosclerosis caused by lipid deposition and endothelial cell (EC) damage through inflammatory cell infiltration [ 4 , 5 ]. This calcification process resembles endochondral ossification as it involves both osteoblasts and chondrocytes, including progressive mineralization of cartilage matrix precursors or primordia [ 6 ].…”