Dual Targeting of Bile Acid Receptor-1 (TGR5) and Farnesoid X Receptor (FXR) Prevents Estrogen-Dependent Bone Loss in Mice

Abstract

Osteoporosis is a global bone disease characterized by reduced bone mineral density (BMD) and increased risk of fractures. The risk of developing osteoporosis increases with aging, especially after menopause in women. Discovering the signaling pathways that play a significant role in aging‐ and menopause‐induced osteoporosis should accelerate osteoporosis drug discovery. In this study, we found that bile acid membrane receptor Tgr5 knockout C57BL/6J mice had similar bone mass as wild‐type mice during early and middle‐age (before 4 months old) bone remodeling; however, Tgr5‐/‐ markedly decreased bone mass in aged (more than 7 months old) and ovariectomized (OVX) mice compared with wild‐type mice. Moreover, Tgr5 knockout strongly induced osteoclast differentiation but had no effect on osteoblast activity. Treatment with different TGR5 agonists consistently inhibited osteoclast differentiation. Importantly, our results showed that Tgr5 regulates osteoclastogenesis by the AMP‐activated protein kinase (AMPK) signaling pathway, which is a central metabolic pathway involved in the pathophysiology of aging and age‐related diseases. The bile acid nuclear receptor FXR is an established regulator of bone metabolism. We screened the derivatives of betulinic acid (BA), a known TGR5 agonist, to identify novel dual agonists of FXR and TGR5. The derivative SH‐479, a pentacyclic triterpene acid, could activate both TGR5 and FXR, with a better inhibitory effect on osteoclastogenesis compared with agonists solely activating FXR or TGR5 and additionally enhanced osteoblastogenesis. Furthermore, SH‐479 therapeutically abrogated bone loss in C57BL/6J mice through the bone remodeling pathways. Together, our results demonstrate that dual targeting the bile acid membrane receptor TGR5 and nuclear receptor FXR is a promising strategy for osteoporosis. © 2018 American Society for Bone and Mineral Research.

Fecal and Serum Metabolomic Signatures and Microbial Community Profiling of Postmenopausal Osteoporosis Mice Model

“…Recent research has shown that osteoporosis is commonly seen among patients with chronic cholestasis (Guañabens and Pareś, 2018), and TGR5 knockout strongly induced osteoclast differentiation in an OP mouse model (Li et al, 2019). Bile acids can also regulate bone turnover, but the functions of specific bile acids are still unclear.…”

Gut microbiome communication with bone marrow regulates susceptibility to amebiasis

“…Bile acid receptors are expressed in many cells implicated in innate immunity, are present in the myeloid lineage, and may impact expansion of these cells ( 8 ). Bone marrow also has the ability to recognize bile acids ( 9 , 10 ). Epigenetic effects may result from signaling via bile acids, including inducing methyltransferase activity ( 11 ).…”

Improving glucose and lipids metabolism: drug development based on bile acid related targets

“…Although many efforts have been made to develop selective FXR or TGR agonists with reduced side effects, research shows that dual agonism of FXR and TGR5 is extremely useful in the treatment of diabetes mellitus, obesity [76], NASH [55,77], atherosclerosis [78], and even other diseases like bone loss [79]. These results demonstrate the potential of FXR/TGR5 dual-targeting agonists as a promising therapy.…”

“…As mentioned before, active triterpene, like Hedragonic acid and BTA, are another kind of molecules being able to activate FXR and TGR5, so it is possible that FXR/TGR5 dual-targeting agonists can be triterpene. Li et al screened 35 BTA derivatives using TGR5-dependent cAMP accumulation and FXR response element reporter gene expression [79]. They found that SH-479, which was first synthesized by Xu et al [82], was a potent TGR5 and FXR dual agonist (Fig.…”