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

Bone and Inflammation

The link between bone and inflammation is evidenced in the process of bone fracture repair, which is, in fact, a true acute inflammatory response of the innate immunity type. At the site of a fracture, bone cells and inflammatory cells are recruited, with resultant intense crosstalk between HSPC (monocyte–macrophage–osteoclast) and MSC (pre-osteoblast–osteoblast) derived cells.[29] T lymphocytes (which can stimulate osteoclastogenesis) and B cells [which can regulate the receptor activator of nuclear factor κB (RANK)/receptor activator of nuclear factor κB ligand (RANKL)/osteoprotegerin (OPG) axis] are also involved, with eventual increases in circulating cytokines.[30] Obviously, this healing process is the same even in the case of asymptomatic microfractures, so that pathologic increases in microfractures can turn into systemic inflammation. Upon reflection, any chronic inflammatory state can be expected to affect bone cell activity, as is illustrated by rheumatoid arthritis (RA), OP and atherosclerosis. In RA, increases in circulating inflammatory cytokines [tumour necrosis factor-alpha (TNF-α), interleukin (IL)-17, RANKL] stimulate osteoclast maturation and activity, thereby increasing bone resorption, while increases in DKK-1 and Sost inhibit bone formation,[31] inducing OP. Ageing, recently regarded as 'inflammaging',[32] i.e. a chronic inflammatory condition, is considered to induce senile OP through similar immunologic mechanisms. Therefore, the link between bone cells and inflammatory cells is well established, as is encapsulated in the new term 'osteoimmunology'.[33] As for the link with CKD, a recent paper has highlighted how CKD could be regarded as a model of accelerated ageing, with resultant bone and cardiovascular disease.[34] Interestingly, according to a recent hypothesis, the link between bone and inflammation may be of evolutionary value in terrestrial animals. This hypothesis suggests that acute inflammation induces a 'sickness behaviour' (malaise, fatigue, anorexia, etc.) that, in the affected animals, is necessary to spare the energy required by the immune response. This adaptive behaviour relies on a complex integrated energetic-neuroendocrine-immune response that includes increased bone resorption to guarantee sufficient amounts of two vital ions like Ca and P, which a resting animal would not be able to gather. This scenario offers support for the importance of the above-mentioned link between bone and energy. Further, one can envisage that, inasmuch as the healing process is incomplete and becomes chronic, it will become maladaptive and responsible for inflammation-related osteopaenia (so-called smoldering inflammation)[35] (Figure 2).

Figure 2.

Bone fracture elicits an acute inflammatory response that is energy demanding and associated with a 'sickness behaviour' usually ending with complete recovery. At variance, multiple diffuse microfractures may lead to chronic subtle inflammation and to osteopaenia.

The link between atherosclerosis, inflammation and bone deserves special consideration. Atherosclerosis is a chronic inflammatory process in all of its stages. The effect of atherosclerosis, as an inflammatory disease, on bone metabolism and the development of OP is suggested by observations confirming that decreased bone mineral density is a good predictor of cardiovascular events and coronary disease in postmenopausal women and men >50 years.[36] Moreover, growing evidence indicates the existence of a correlation between OP and atherosclerosis regardless of age, body mass index and cardiovascular risk factors[37] . Furthermore, chronic inflammatory processes contribute to vascular calcification, and the common finding of simultaneous vascular calcification and OP in individual patients suggests that local tissue factors govern the regulation of biomineralization.[38] New terms like 'calcification paradox'[39] and 'osteocardiology'[40] are being coined to illustrate this clinical link. Vascular calcification in atherosclerosis is triggered by the response to injury caused by oxidized low-density lipoprotein (LDLox). LDLox initiates the inflammatory process, which is amplified by the exposure of adhesion molecules and by the secretion of interleukins, C-reactive protein (CRP) and bone morphogenetic proteins (BMPs) by endothelial cells and smooth muscle cells. All these processes promote increased oxidative stress and decreased calcification inhibitors, such as matrix Glutamic acid (Gla)-protein and osteopontin. Experimental evidence implies that atherosclerotic inflammatory activity has an interrelationship with osteogenic modulation. When exposed to LDLox, endothelial cells express BMPs. Additionally, TNF-α and interferon-gamma stimulate the endothelium to express OPG, which is also produced in osteoblasts and in smooth muscle cells when stimulated with proinflammatory interleukins.[41] Hyperproduction of inflammatory markers such as CRP, IL-1, IL-6 and TNF-α is directly related to the severity of atherosclerosis and the stimulation of osteoclastogenesis.[42]

Monocytes and macrophages (after HSPC recruitment from BM) are the dominant type of atherosclerotic inflammatory cell infiltrates and represent more than half of all cells at the immediate site of plaque rupture. Furthermore, leakage of cytokines and leukotrienes from activated macrophages in the atherosclerotic plaque enriches the systemic proinflammatory milieu.[43] Another implicated factor is endothelium-derived nitric oxide (NO), which is reduced at the site of vascular injury. Indeed, NO inhibits platelet adherence and aggregation, suppresses vasoconstriction, reduces the adherence of leucocytes to the endothelium, and suppresses the proliferation of vascular smooth muscle cells. Therefore, a reduction in NO activity contributes to a proinflammatory and prothrombotic milieu.

In CKD, an increase in the inflammatory biomarkers TNF-α, IL-6, IL-1, CRP and fibrinogen has been reported in the blood.[44] This increase is caused by several mechanisms, including reduced clearance of proinflammatory cytokines, increased local production (e.g. due to the blood–membrane contact in dialysis patients), pathologic permeability of gut to toxins (so-called leaky gut syndrome) and induction of macrophage activation by metabolic acidosis.[45–47] Monocytes and macrophages are increased in the peripheral blood of uraemic patients even when there is no clinical evidence of an active inflammatory process or an increase in the peripheral blood of other inflammatory markers, such as CRP or proinflammatory cytokines.[48] Further, in CKD the mitochondrial respiratory system is impaired, which may be both a consequence and a cause of enhanced oxidative stress. Through elevated production of reactive oxygen species (ROS), the damaged mitochondria of uraemic patients may be able to activate the NLRP3 inflammasome, a deregulated biological system newly identified in CKD-5D patients.[49–52] Increased generation of ROS in chronic renal failure can damage proteins, lipids and nucleic acids and consequently influence cell function, inhibit enzymatic activities of the cellular respiratory chain and accelerate progression of CKD.[53] Changes in oxidative and antioxidant status, which occur from the early stages of CKD, may be exacerbated by haemodialysis.[54,55] Therefore, oxidative stress and chronic inflammation are both important players in the mechanisms underlying CKD-related accelerated atherogenesis and ageing.[34] In turn, accelerated atherogenesis will negatively affect bone metabolism (Figure 3).

Figure 3.

CKD is a chronic inflammatory state with increased circulating pro-inflammatory cytokines (IL-17, TNF-α, RANKL, BMPs, etc.) and decreased calcification inhibitors (MGP, OPN, etc.). Circulating monocytes and enhanced oxidative stress (via the NLRP3 inflammasome) accelerate atherogenesis. Local response to the injury caused by LDLox is amplified by exposure of adhesion molecules and secretion of interleukins and BMP by endothelial cells and smooth muscle cells. All these processes further increase systemic oxidative stress, decrease calcifying inhibitors and promote vessel wall calcification. ROD, by interfering with BM niche function, is expected to contribute to this systemic microinflammatory burden that accelerates atherosclerosis, vessel calcification and osteopaenia.

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