Core level regulatory network of osteoblast as molecular mechanism for osteoporosis and treatment

Abstract

To develop and evaluate the long-term prophylactic treatment for chronic diseases such as osteoporosis requires a clear view of mechanism at the molecular and systems level. While molecular signaling pathway studies for osteoporosis are extensive, a unifying mechanism is missing. In this work, we provide experimental and systems-biology evidences that a tightly connected top-level regulatory network may exist, which governs the normal and osteoporotic phenotypes of osteoblast. Specifically, we constructed a hub-like interaction network from well-documented cross-talks among estrogens, glucocorticoids, retinoic acids, peroxisome proliferatoractivated receptor, vitamin D receptor and calcium-signaling pathways. The network was verified with transmission electron microscopy and gene expression profiling for bone tissues of ovariectomized (OVX) rats before and after strontium gluconate (GluSr) treatment. Based on both the network structure and the experimental data, the dynamical modeling predicts calcium and glucocorticoids signaling pathways as targets for GluSr treatment. Modeling results further reveal that in the context of missing estrogen signaling, the GluSr treated state may be an outcome that is closest to the healthy state.

Medical Treatment for Osteoporosis: From Molecular to Clinical Opinions

“…Transgenic and knockout mouse models have been employed for studying human osteoporosis, due to the similarities between human and mice genomes [5]; the ovariectomized rat model mimics osteoporosis [3,6]. Senescence-accelerated mouse prone 6 (SAMP6) mice have reduced osteoblastic bone formation, which may be due to the upregulation of the transcription factor peroxisome proliferator activator gamma (PPARγ).…”

“…Finally, a cross-linked core molecular network structure could serve as a unified molecular mechanism for different phenotypes of osteoblasts [6]. Apart from genetic factors, hypovitaminosis D is also known to increase the risk of osteoporosis [11].…”

“…Because these agents are either suboptimal or cause significant side effects, current research is attempting to develop new drugs or modify existing drugs. This review includes the literature on transgenic and knockout mouse models [5,7], a hypothesis of a cross-linked core molecular network structure [6], in silico analyses [4], candidate gene association studies, genome-wide linkage and association studies, functional genomic studies, gene expression microarray studies, and proteomics [5].…”

“…PPARs are members of a nuclear receptor family that form a complex with the retinoid X receptor (RXR) and function as transcription factors to regulate the expression of genes. PPARs are involved in major metabolic processes as well as cell proliferation, differentiation, and survival [6]. Due to its likely role in regulating the direction of BMSC lineage, PPARγ is regarded as a promising target for osteoporosis therapy, however, its precise mechanism remains unknown.…”

Let‐7b downgrades CCND1 to repress osteogenic proliferation and differentiation of MC3T3‐E1 cells: An implication in osteoporosis

“…4 Among them, estrogen, glucocorticoid and retinoic acid all exert their regulatory effects on OP through the overlapping molecular machinery of molecular transcription and translation, signal transduction. 5 MicroRNAs (miRNAs), as important small molecule are regulatory, are a type of small noncoding RNA and the length is approximately 22 nucleotides. 6 MiRNAs take part in many biological processes, including cell differentiation and cycle progression, cell proliferation, and so on.…”