Bone marrow-derived mesenchymal stem cells (BMSCs) are widely used in regenerative medicine in light of their ability to differentiate along the chondrogenic and osteogenic lineages. As a type of traditional Chinese medicine, quercetin has been preliminarily reported to promote osteogenic differentiation in osteoblasts. In the present study, the effects of quercetin on the proliferation, viability, cellular morphology, osteogenic differentiation and angiogenic factor secretion of rat BMSCs (rBMSCs) were examined by MTT assay, fluorescence activated cell sorter (FACS) analysis, real-time quantitative PCR (RT-PCR) analysis, alkaline phosphatase (ALP) activity and calcium deposition assays, and Enzyme-linked immunosorbent assay (ELISA). Moreover, whether mitogen-activated protein kinase (MAPK) signaling pathways were involved in these processes was also explored. The results showed that quercetin significantly enhanced the cell proliferation, osteogenic differentiation and angiogenic factor secretion of rBMSCs in a dose-dependent manner, with a concentration of 2 μM achieving the greatest stimulatory effect. Moreover, the activation of the extracellular signal-regulated protein kinases (ERK) and p38 pathways was observed in quercetin-treated rBMSCs. Furthermore, these induction effects could be repressed by either the ERK inhibitor PD98059 or the p38 inhibitor SB202190, respectively. These data indicated that quercetin could promote the proliferation, osteogenic differentiation and angiogenic factor secretion of rBMSCs in vitro, partially through the ERK and p38 signaling pathways.

Bone regeneration under osteoporotic conditions with impaired angiogenesis, osteogenesis and remodeling represents a great challenge. In the present study, the effects of quercetin on proliferation, osteogenic differentiation and angiogenic factor secretion as well as on the osteoclastogenic factor secretion of ovariectomized (OVX) rat bone marrow-derived mesenchymal stem cells (rBMSCs) were first evaluated in vitro. The role of mitogen-activated protein kinase (MAPK) signaling pathways and the protein kinase B (AKT) signaling pathway in these processes was also investigated. Finally, hydroxyapatite (HA) bioceramic microspheres with a micro–nano hybrid surface (nHA bioceramic microspheres) were fabricated and used as drug delivery carriers of quercetin, and the ability to induce osteogenesis and angiogenesis in vivo was confirmed in an OVX rat critical-sized femur defect model. In vitro studies showed that quercetin significantly promoted cell proliferation, ALP activity and the expression of osteogenic and angiogenic factors of OVX rBMSCs as well as inhibited the expression of receptor activator of nuclear factor-κB ligand (RANKL) in a dose-dependent manner, with a concentration of 1 μM yielding the greatest effect. Moreover, the activation of the extracellular signal-regulated protein kinase (ERK), p38 and AKT signaling pathways was observed in quercetin-treated OVX rBMSCs, and the crosstalk among these signaling pathways was evident. Furthermore, the nHA bioceramic microspheres could efficiently release quercetin in a sustained manner, and quercetin loaded in the nHA bioceramic microspheres could promote new bone formation and blood vessel formation in vivo. The present study revealed that quercetin could promote osteogenesis and angiogenesis while inhibiting osteoclastogenesis both in vitro and in vivo under osteoporotic conditions. Moreover, HA bioceramic microspheres with a micro–nano hybrid surface could act as injectable drug delivery carriers of quercetin and could be applied for osteoporotic bone regeneration.

Typically, bone regenerative medicine is applied to repair bone defects in patients with osteoporosis. Meanwhile, there is an urgent need to develop safe and cheap drugs that induce bone formation. Icariin, which is reported to promote the osteogenesis of stem cellsin vitro, is the main active component ofHerba Epimedii. However, whether icariin could repair bone defects caused by osteoporosis remains unknown. In this study, an osteoporosis model in rats was established by an ovariectomy first, and then, the osteogenic and angiogenic differentiation of bone mesenchymal stem cells (BMSCs) treated with icariin was evaluated. Furthermore, calcium phosphate cement (CPC) scaffolds loaded with icariin were constructed and then implanted into nude mice to determine the optimal construction. To evaluate its osteogenic and angiogenic abilityin vivo, this construction was applied to calvarial defect of the ovariectomized (OVX) rats accompanied with an icariin gavage. This demonstrated that icariin could up-regulate the expression of osteogenic and angiogenic genes in BMSCs. Meanwhile, osteoclast formation was inhibited. Moreover, CPC could act as a suitable icariin delivery system for repairing bone defects by enhancing osteogenesis and angiogenesis, while the systemic administration of icariin has an antiosteoporotic effect that promotes bone defect repair.

Periodontal disease ranks third among noncommunicable illnesses, behind cancer and cardiovascular disease, and is closely related to the occurrence and progression of various systemic diseases. However, elucidating the processes of periodontal disease and promoting periodontal bone regeneration remains a challenge. Here, quercetin is demonstrated to reduce the oxidative stress state of orofacial mesenchymal stem cells (OMSCs) in vitro and to affect the osteogenic growth of OMSCs through molecular mechanisms that mediate the m6A change in Per1. Nevertheless, the limited therapeutic efficacy of systemic medication and the limitations of local medication resulting from the small, moist, and highly dynamic periodontal environment make it challenging to treat periodontal tissues with medication. Herein, a biosafe injectable hydrogel drug‐controlled delivery system is constructed as a bone‐enhancing factory and loaded with quercetin to treat oxidative stress injury in periodontal tissues. This drug‐carrying system made up of nanoscale bioglass microspheres and a light‐cured injectable hydrogel, allows effective drug particle loading and cementation in the dynamic and moist periodontal environment. Furthermore, the system demonstrates the ability to stimulate OMSCs osteogenic differentiation in a Per1‐dependent manner, which ultimately promotes periodontal bone repair, suggesting that this system has potential for clinical periodontal therapy.