Ca_v1.2 regulates osteogenesis of bone marrow‐derived mesenchymal stem cells via canonical Wnt pathway in age‐related osteoporosis

Abstract

Aims Age‐related bone mass loss is one of the most prevalent diseases that afflict the elderly population. The decline in the osteogenic differentiation capacity of bone marrow‐derived mesenchymal stem cells (BMMSCs) is regarded as one of the central mediators. Voltage‐gated Ca2+ channels (VGCCs) play an important role in the regulation of various cell biological functions, and disruption of VGCCs is associated with several age‐related cellular characteristics and systemic symptoms. However, whether and how VGCCs cause the decreased osteogenic differentiation abilities of BMMSCs have not been fully elucidated. Methods Voltage‐gated Ca2+ channels related genes were screened, and the candidate gene was determined in several aging models. Functional role of determined channel on osteogenic differentiation of BMMSCs was investigated through gain and loss of function experiments. Molecular mechanism was explored, and intervention experiments in vivo and in vitro were performed. Results We found that Cav1.2 was downregulated in these aging models, and downregulation of Cav1.2 in Zmpste24−/− BMMSCs contributed to compromised osteogenic capacity. Mechanistically, Cav1.2 regulated the osteogenesis of BMMSCs through canonical Wnt/β‐catenin pathway. Moreover, upregulating the activity of Cav1.2 mitigated osteoporosis symptom in Zmpste24−/− mice. Conclusion Impaired osteogenic differentiation of Zmpste24−/− BMMSCs can be partly attributed to the decreased Cav1.2 expression, which leads to the inhibition of canonical Wnt pathway. Bay K8644 treatment could be an applicable approach for treating age‐related bone loss by ameliorating compromised osteogenic differentiation capacity through targeting Cav1.2 channel.

Extracellular IL-37 promotes osteogenic differentiation of human bone marrow mesenchymal stem cells via activation of the PI3K/AKT signaling pathway

“…To explore the underlying signaling pathways involved in the regulation of BMSC differentiation by IL-37, several most common signaling pathways involved in osteogenesis, including the β-catenin, mitogen-activated protein kinase (MAPK)/p38, and PI3K/AKT signaling pathways, were examined by western blotting. Increased expression of p-AKT was observed in the IL-37 group (0.01–100 ng/ml) on day 3 26–29 of osteogenic differentiation, whereas no significant differences were found in the protein levels of t-AKT, p-p38, t-p38, and β-catenin among these groups (Fig. 3a, b).…”

Calcium channelopathies and intellectual disability: a systematic review

“…H9C2 and rat myocytes in long QT syndrome type 2 [ 296 ]. Timothy syndrome cardiomyocytes for cardiac arrhythmias [ 174 ] Micro-RNA-137 targets the CACNA1C in mice and human neuroblastoma cells for Alzheimer's disease [ 167 ] MiR-221 and -222 inhibit Cav1.2 current in HL-1 cells [ 168 ] Nifedipine and benidipine hydrochloride inhibited severe fever with thrombocytopenia syndrome in Huh7 cells and in humanized mouse model [ 171 ] MiR-153 inhibitors upregulate the expression of Cacna1c mRNA and protein [ 169 ] Bay K8644 can prevent age related bone loss [ 173 ] MiR-103 can suppress expression of Cav1.2 and thus inhibit osteoblast proliferation [ 170 ] Estradiol can upregulates expression of Cav1.2 [ 148 ] Roscovitine could rescue cardiac arrhythmias [ 174 ] Stac2 and Stac3 can modulate CaV1.2 function [ 175 ] Azelnidipine reduces the expression of Cav1.2 [ 176 ] Wnt pathway for age‐related osteoporosis [ 173 ] Apoptotic pathway in lymphoma [ 172 ] Apoptotic pathway in melanoma [ 192 ] Autophagic pathway in autism [ 197 ] CACNA1D Calcium voltage-gated channel subunit alpha1 D Cav1.3 L-type TsA-201 cells for ID and autism [ 82 , 84 ] TsA-201 cells in hearing [ 297 ]. Rat hippocampal and HEK293 cells for Alzheimer's disease [ 298 ] Isradipine could block Cav1.3 current in vitro [ 84 ] Apoptotic pathway [ 127 ] CACNA1E Calcium voltage-gated channel subunit alpha1 E Cav2.3 R-type TsA201 cells for ID and epilepsy [ 85 ] None Sipatrigine, eugenol, and lamotrigine could block Cav2.3 current [ 177 , …”

“…Bay K8644 can prevent age related bone loss [ 173 ]…”

Osteoimmunology: The Regulatory Roles of T Lymphocytes in Osteoporosis

“…Aging is always accompanied with the imbalance between bone formation and resorption, causing skeletal microarchitecture damage and bone loss (59). The production of naïve T cells is severely impaired due to a decreased output of lymphoid cells from the bone marrow and the deterioration of the thymus (60).…”