Inhibition of the estrogen receptor alpha signaling delays bone regeneration and alters osteoblast maturation, energy metabolism, and angiogenesis

Wu, Gong-Jhe; Chen, Jui-Tai; Lin, Pei-I; Cherng, Yih-Giun; Yang, Shun-Tai; Chen, Ruei-Ming

Affiliations

¹Department of Anesthesiology, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan

²Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan

³Department of Anesthesiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan

⁴Department of Neurosurgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan

⁵Cell Physiology and Molecular Image Research Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan

⁶Anesthesiology and Health Policy Research Center, Taipei Medical University Hospital, Taipei, Taiwan

⁷TMU Research Center of Cancer Translational Medicine, Taipei, Taiwan

Abstract and keywords

Aims: The estrogen-ERα axis participates in osteoblast maturation. This study was designed to further evaluated the roles of the estrogen-ERα axis in bone healing and the possible mechanisms.

Main methods: Female ICR mice were created a metaphyseal bone defect in the left femurs and administered with methylpiperidinopyrazole (MPP), an inhibitor of ERα. Bone healing was evaluated using micro-computed tomography. Colocalization of ERα with alkaline phosphatase (ALP) and ERα translocation to mitochondria were determined. Levels of ERα, ERβ, PECAM-1, VEGF, and β-actin were immunodetected. Expression of chromosomal Runx2, ALP, and osteocalcin mRNAs and mitochondrial cytochrome c oxidase (COX) I and COXII mRNAs were quantified. Angiogenesis was measured with immunohistochemistry.

Key findings: Following surgery, the bone mass was time-dependently augmented in the bone-defect area. Simultaneously, levels of ERα were specifically upregulated and positively correlated with bone healing. Administration of MPP to mice consistently decreased levels of ERα and bone healing. As to the mechanisms, osteogenesis was enhanced in bone healing, but MPP attenuated osteoblast maturation. In parallel, expressions of osteogenesis-related ALP, Runx2, and osteocalcin mRNAs were induced in the injured zone. Treatment with MPP led to significant inhibition of the alp, runx2, and osteocalcin gene expressions. Remarkably, administration of MPP lessened translocation of ERα to mitochondria and expressions of mitochondrial energy production-related coxI and coxII genes. Furthermore, exposure to MPP decreased levels of PECAM-1 and VEGF in the bone-defect area.

Significance: The present study showed the contributions of the estrogen-ERα axis to bone healing through stimulation of energy production, osteoblast maturation, and angiogenesis.

Keywords: Bone healing; Estrogen-ERα axis; Osteoblast maturation; Angiogenesis; Energy production

Links

DOI: 10.1016/j.lfs.2020.118195

PubMed: 32781073

WoS: 000575171200013

History

Received: 2020-06-17

Revised: 2020-07-27

Accepted: 2020-07-31

Online: 2020-08-08

Cited Works (5)

Year	Entry
2014	Kusumbe AP, Ramasamy SK, Adams RH. Coupling of angiogenesis and osteogenesis by a specific vessel subtype in bone. Nature. March 20, 2014;507(7492):323-328.
2006	Seeman E, Delmas PD. Bone quality: the material and structural basis of bone strength and fragility. NEJM. May 25, 2006;354(21):2250-2261.
2009	Holzer G, von Skrbensky G, Holzer LA, Pichl W. Hip fractures and the contribution of cortical versustrabecular bone to femoral neck strength. J Bone Miner Res. March 2009;24(3):468-474.
2003	Eghbali-Fatourechi G, Khosla S, Sanyal A, Boyle WJ, Lacey DL, Riggs BL. Role of RANK ligand in mediating increased bone resorption in early postmenopausal women. J Clin Invest. April 2003;111(8):1221-1230.
2009	Bliuc D, Nguyen ND, Milch VE, Nguyen TV, Eisman JA, Center JR. Mortality risk associated with low-trauma osteoporotic fracture and subsequent fracture in men and women. JAMA. February 4, 2009;301(5):513-521.