Can Polymorphisms in NLRP3 Inflammasome Complex Be Associated with Postmenopausal Osteoporosis Severity?

Abstract

The immune system plays a critical role in bone homeostasis and, consequently, in the pathophysiology of postmenopausal osteoporosis (OP) since estrogen deficiency induces the inflammasome and increases production of pro-inflammatory cytokines, such as IL-1β and IL-18. NLRP3 inflammasome complex genes have been related with bone homeostasis in cellular and animal models. Here, we performed an association study evaluating SNVs (single-nucleotide variants) in inflammasome NLRP3 pathway genes (NLRP3, CARD8, CASP1, IL-18, and IL-1β) to assess whether variants in these genes could be related to susceptibility to primary OP in postmenopausal women. Methods: We genotyped 196 postmenopausal OP patients and 103 healthy controls using SNV-specific Taqman® probes. Data and statistical analyses were performed using the SNPstats and GraphPad Prism 8 software. Results: We showed an association between NLRP3 rs35829419 CA genotype and lower bone mineral density (BMD) mean at the lumbar spine (p = 0.001); we also observed an association between IL-1β rs16944 AA genotype and higher BMD mean at the total hip (p = 0.009). The IL-1β rs16944 GG was associated with lower alkaline phosphatase levels (ALP) (p = 0.009), and the IL-18 rs1946519 AA was associated with lower vitamin D levels (p = 0.018). Additionally, OP patients presented deficient vitamin D and parathyroid hormone (PTH). Conclusions: The NLRP3 inflammasome complex SNVs were associated with OP severity, possibly indicating these genes’ participation in bone metabolism and its dysregulation.

Molecular and Cellular Mechanisms of Osteoporosis

“…NLRP3 inflammasome plays an important role in the development of osteoporosis by reducing differentiation, causing dysfunction of the osteoblasts, and accelerating osteoclasts, thus promoting bone resorption and impaired bone formation [122]. The study in postmenopausal women with osteoporosis demonstrated that single-nucleotide variants in NLRP3 inflammasome pathway genes activating pro-inflammatory cytokines IL-1β and IL-18 production are associated with osteoporosis severity [123]. Increased secretion of inflammatory cytokines, in particular, TNF-α and IL-1β, induces MAPK activation that leads to reduced osteoblastogenesis, resulting in defective bone remodeling [124].…”