Role of Sclerostin in Cardiovascular System

Abstract

Sclerostin, encoded by the SOST gene, is a novel bone anabolic target for bone diseases. Humanized anti-sclerostin antibody, romosozumab, was approved for treatment of postmenopausal osteoporosis by the US Food and Drug Administration (FDA), but with a black-box warning on cardiovascular risk. The clinical data regarding cardiovascular events from various pre-marketing and post-marketing studies of romosozumab were inconsistent. Overall, the cardiovascular risk of sclerostin inhibition could not be excluded. The restriction of romosozumab in patients with cardiovascular disease history would be necessary. Moreover, genome-wide association study (GWAS) analyses of SOST variants revealed inconsistent results of the association between SOST variations and cardiovascular diseases. Further research incorporating larger sample sizes and functional analyses are necessary. In analyses of serum/tissue sclerostin levels in patients with cardiovascular diseases, the results were controversial but indicated an association between sclerostin and the presence/severity/outcomes of cardiovascular diseases. Nonclinical studies in rodents indicated the inhibitory effect of sclerostin on inflammation, aortic aneurysm, atherosclerosis, and vascular calcification. Sclerostin loop3 participated in the inhibitory effect of sclerostin on bone formation, while the cardiovascular protective effect of sclerostin was independent of sclerostin loop3. Macrophagic sclerostin loop2-apolipoprotein E receptor 2 (ApoER2) interaction participated in the inhibitory effect of sclerostin on inflammation in vitro. Sclerostin in human aortic smooth muscle cells participated in the reduction in calcium deposition. The role of sclerostin in cardiovascular system deserves further investigation.

Keywords: cardiovascular system; clinical data; molecular understanding; nonclinical data; sclerostin.

Figure 1

The illustration of three-dimensional structure of sclerostin. (a) Ribbon drawing of the solution structure of sclerostin (PBD ID: 2K8P). Long N- and C-terminal regions are highly flexible. Other residues formed three loop-like domains (green: loop 1; red: loop 2; yellow: loop 3). Six cysteine residues are highlighted in blue. (b) Potential active sites on loop 3 of sclerostin. Positive charged residues (K and R) and labeled in blue and their side chains are shown in sticks. Hydrophobic residues (V and L) are labeled in black. These residues are included in the positive target of virtual screening. (c) Motifs on loop 2 that bind to discovered sclerostin inhibitors. Residues N93-R102 are labeled in black, including potential interaction sites between sclerostin and inhibitors.

Figure 2

Sclerostin exhibited protective effect on the cardiovascular system. (a) The sclerostin antibody induced inhibition of sclerostin’s suppressive effect on atherosclerosis progression (left) in ApoE^−/− mice, while this inhibition was abolished by supplement of exogenous loop2m (right). (b) Adenine-exposed Sost^−/− mice exhibited greater calcification in the cardiac vessels (right) than adenine-exposed WT mice (left). (c) Sclerostin in macrophages/VSMCs participated in inhibiting inflammatory responses and vascular calcification development. Sclerostin overexpression in VSMCs decreased calcium deposits in a calcified environment and downregulated the expression of inflammatory genes such as IL1β, IL6, and IL8 (left). The addition of sclerostin in macrophages exhibited suppressive effects on inflammatory responses and mediated the conversion of the macrophages into anti-inflammatory M2 phenotypes (right). Abbreviations: Loop2m: loop2 mutant; AA: aortic aneurysm. Note: The upward arrows “↑” in the figure represented increase or upregulation. The downward arrows “↓” in the figure represented decrease or downregulation.