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A new osteogenic protein isolated from Dioscorea opposita Thunb accelerates bone defect healing through the mTOR signaling axis

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Bioactive Materials 2023年第9期27卷 429-446页

作者： John Akrofi Kubi augustine suurinobah brah Kenneth Man Chee Cheung Yin Lau Lee Kai-Fai Lee Stephen Cho Wing Sze Wei Qiao Kelvin Wai-Kwok Yeung Department of Orthopaedics and Traumatology Li Ka Shing Faculty of MedicineThe University of Hong Kong(HKU)Hong Kong S.A.R.PR China Shenzhen Key Laboratory for Innovative Technology in Orthopaedic Trauma HKU-Shenzhen HospitalShenzhen518053PR China Department of Obstetrics and Gynaecology Li Ka Shing Faculty of MedicineHKU21 Sassoon RoadHong Kong S.A.RPR China Shenzhen Key Laboratory of Fertility Regulation Reproductive Medicine CenterHKU-Shenzhen HospitalShenzhenPR China Department of Biology Faculty of ScienceHong Kong Baptist UniversityKowloon TongHong Kong S.A.RPR China Golden Meditech Center for NeuroRegeneration Sciences Hong Kong Baptist UniversityKowloon TongHong Kong S.A.RPR China Applied Oral Sciences and Community Dental Care Faculty of DentistryHong Kong S.A.RPR China

Delayed bone defect repairs lead to severe health and socioeconomic impacts on patients. Hence, there are increasing demands for medical interventions to promote bone defect healing. Recombinant proteins such as BMP-2 have been recognized as one of the powerful osteogenic substances that promote mesenchymal stem cells (MSCs) to osteoblast differentiation and are widely applied clinically for bone defect repairs. However, recent reports show that BMP-2 treatment has been associated with clinical adverse side effects such as ectopic bone formation, osteolysis and stimulation of inflammation. Here, we have identified one new osteogenic protein, named ‘HKUOT-S2’ protein, from Dioscorea opposita Thunb. Using the bone defect model, we have shown that the HKUOT-S2 protein can accelerate bone defect repair by activating the mTOR signaling axis of MSCs-derived osteoblasts and increasing osteoblastic biomineralization. The HKUOT-S2 protein can also modulate the transcriptomic changes of macrophages, stem cells, and osteoblasts, thereby enhancing the crosstalk between the polarized macrophages and MSCs-osteoblast differentiation to facilitate osteogenesis. Furthermore, this protein had no toxic effects in vivo. We have also identified HKUOT-S2 peptide sequence TKSSLPGQTK as a functional osteogenic unit that can promote osteoblast differentiation in vitro. The HKUOT-S2 protein with robust osteogenic activity could be a potential alternative osteoanabolic agent for promoting osteogenesis and bone defect repairs. We believe that the HKUOT-S2 protein may potentially be applied clinically as a new class of osteogenic agent for bone defect healing.

关键词： Dioscorea spp protein Mesenchymal stem cells(MSCs) Osteoblast differentiation Bone mineral density(BMD) Bone defect repair mTOR signaling pathway

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Low-molecular-weight estrogenic phytoprotein suppresses osteoporosis development through positive modulation of skeletal estrogen receptors

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Bioactive Materials 2024年第12期42卷 299-315页

作者： John Akrofi Kubi augustine suurinobah brah Kenneth Man Chee Cheung Andy Chun Hang Chen Yin Lau Lee Kai-Fai Lee Wei Qiao Yibin Feng Kelvin Wai Kwok Yeung Department of Orthopaedics and Traumatology Li Ka Shing Faculty of MedicineThe University of Hong Kong(HKU)PR China Shenzhen Key Laboratory for Innovative Technology in Orthopaedic Trauma HKU-Shenzhen HospitalShenzhen518053PR China Department of Obstetrics and Gynaecology Li Ka Shing Faculty of MedicineHKU21 Sassoon RoadPR China Shenzhen Key Laboratory of Fertility Regulation Reproductive Medicine CenterHKU-Shenzhen HospitalShenzhenPR China Applied Oral Sciences and Community Dental Care Faculty of DentistryPR China School of Chinese Medicine Li Ka Shing Faculty of MedicineThe University of Hong Kong(HKU)PR China

Age-related osteoporosis is a metabolic skeletal disorder caused by estrogen deficiency in postmenopausal *** use of anti-osteoporotic drugs such as bisphosphonates and FDA-approved anti-resorptive selective estrogen receptor modulators(SERMs)has been associated with various clinical *** recently discovered a low-molecular-weight biocompatible and osteoanabolic phytoprotein,called HKUOT-S2 protein(32 kDa),from Dioscorea opposita Thunb that can accelerate bone defect ***,we demonstrated that the HKUOT-S2 protein treatment can enhance osteoblasts-induced ossification and suppress osteoporosis development by upregulating skeletal estrogen receptors(ERs)ERα,ERβ,and GPR30 expressions in ***,HKUOT-S2 protein estrogenic activities promoted hMSCs-osteoblasts differentiation and functions by increasing osteogenic markers,ALP,and RUNX2 expressions,ALP activity,and osteoblast biomineralization in *** treatment impaired the HKUOT-S2 protein-induced ERs expressions,osteoblasts differentiation,and ***,we demonstrated that the HKUOT-S2 protein could bind to ERs to exert osteogenic and osteoanabolic *** results showed that the biocompatible HKUOT-S2 protein can exert estrogenic and osteoanabolic properties by positively modulating skeletal estrogen receptor signaling to promote ossification and suppress ***,there is no or limited data if any,on osteoanabolic *** HKUOT-S2 protein can be applied as a new osteoanabolic SERM for osteoporosis treatment.

关键词： Ovariectomy(ovx) Osteoporosis Osteoblast functions Estrogen receptors(ERs) HKUOT-S2 protein

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