Higenamine Promotes Osteogenesis Via IQGAP1/SMAD4 Signaling Pathway and Prevents Age- and Estrogen-Dependent Bone Loss in Mice

Abstract

Osteoporosis is a common bone disease caused by an imbalance of bone resorption and formation that results in a loss of total bone density. SMAD2/3 signal transduction is known to play a crucial role in osteogenic differentiation through transforming growth factor-beta (TGF-β). By screening a library of small-molecule compounds, the current study identifies higenamine (HG) as an active osteogenic agent that could be a therapeutic candidate for osteoporosis. In vitro data demonstrated that HG effectively induced expressions of osteogenic markers in mouse bone marrow stromal cell (BMSCs) and preosteoblastic cell cultures. Further, HG treatment resulted in enhanced bone formation and prevented accelerated bone loss on two animal models that mimic spontaneous senile osteoporosis and postmenopausal osteoporosis. IQ motif-containing GTPase-activating protein 1 (IQGAP1) was confirmed as a novel target of HG, where HG appears to bind to the Glu-1019 site of IQGAP1 to exert its osteogenic effects. Data subsequently suggested that HG promoted phosphorylation of SMAD2/3 and regulated the SMAD2/3 pathway by inhibiting SMAD4 ubiquitination. Overall, the findings highlight HG as a new small-molecule drug to promote bone formation through SMAD2/3 pathway in osteoporosis.

Cell signaling and transcriptional regulation of osteoblast lineage commitment, differentiation, bone formation, and homeostasis

“…Higenamine (HG) has been recognized as a promising candidate for treating osteoporosis through its influence on SMAD2/3 signaling. A novel target for HG has been identified in IQ motif-containing GTPase activating protein 1 (IQGAP1), with HG binding to the Glu-1019 site of IQGAP1, facilitating its osteogenic effects 120 . Through this mechanism, HG induces Smad2/3 phosphorylation and modulates the Smad2/3 pathway by inhibiting Smad4 ubiquitination 120 .…”

“…A novel target for HG has been identified in IQ motif-containing GTPase activating protein 1 (IQGAP1), with HG binding to the Glu-1019 site of IQGAP1, facilitating its osteogenic effects 120 . Through this mechanism, HG induces Smad2/3 phosphorylation and modulates the Smad2/3 pathway by inhibiting Smad4 ubiquitination 120 . Consequently, HG emerges as a potential novel small-molecule drug to stimulate bone formation in osteoporosis via the Smad2/3 pathway 120 .…”

“…Through this mechanism, HG induces Smad2/3 phosphorylation and modulates the Smad2/3 pathway by inhibiting Smad4 ubiquitination 120 . Consequently, HG emerges as a potential novel small-molecule drug to stimulate bone formation in osteoporosis via the Smad2/3 pathway 120 .…”

Atsttrin regulates osteoblastogenesis and osteoclastogenesis through the TNFR pathway

“…Bone matrix homeostasis is a dynamically balanced system that is maintained by a balance between bone formation by osteoblasts and bone resorption by osteoclasts 1 , 2 . Osteoblasts are derived from mesenchymal precursor cells and are responsible for the deposition of new bone matrix to facilitate bone mineralization during bone reconstruction 3 , 4 . Osteoclasts, on the other hand, are giant multinucleated cells derived from the bone marrow monocyte lineage that play an important role in reabsorbing mineralized matrix 5 , 6 .…”