Ophiopogonin D promotes bone regeneration by stimulating CD31^hiEMCN^hi vessel formation

Abstract

Objectives CD31hiEMCNhi vessels (CD31, also known as PECAM1 [platelet and endothelial cell adhesion molecule 1]; EMCN, endomucin), which are strongly positive for CD31 and endomucin, couple angiogenesis and osteogenesis. However, the role of CD31hiEMCNhi vessels in bone regeneration remains unknown. In the present study, we investigated the role of CD31hiEMCNhi vessels in the process of bone regeneration. Materials and Methods We used endothelial‐specific Krüppel like factor 3 (Klf3) knockout mice and ophiopogonin D treatment to interfere with CD31hiEMCNhi vessel formation. We constructed a bone regeneration model by surgical ablation of the trabecular bone. Immunofluorescence and micro‐computed tomography (CT) were used to detect CD31hiEMCNhi vessels and bone formation. Results CD31hiEMCNhi vessels participate in the process of bone regeneration, such that endothelial‐specific Klf3 knockout mice showed increased CD31hiEMCNhi vessels and osteoprogenitors in the bone regeneration area, and further accelerated bone formation. We also demonstrated that the natural compound, ophiopogonin D, acts as a KLF3 inhibitor to promote vessels formation both in vitro and in vivo. Administration of ophiopogonin D increased the abundance of CD31hiEmcnhi vessels and accelerated bone healing. Conclusions Our findings confirmed the important role of CD31hiEmcnhi vessels in bone regeneration and provided a new target to treat bone fracture or promote bone regeneration.

Bone Vasculature and Bone Marrow Vascular Niches in Health and Disease

“…( 214 ) Treatment with ophiopogonin D, a Krüppel‐like factor‐3 (KLF3) inhibitor, enhances the abundance of type H vessels and accelerates bone healing. ( 215 ) A novel poly‐GLP‐1 molecule using a polymeric pro‐drug strategy was found to increase the number of type H ECs and promote bone formation in a mouse femoral defect model. ( 216 )…”

Unique bone marrow blood vessels couple angiogenesis and osteogenesis in bone homeostasis and diseases

“…A recent study also confirmed the critical role of type H vessels in bone fracture healing, as type H vessels reappeared in the bone repair area of aged mice, together with increased osteoprogenitors and bone volume. 79 Furthermore, Ji et al also reported that the VEGF pathway mediated type H vessel angiogenesis and osseointegration in periimplant bone following injury. 80,81 Pharmacological blockade of the VEGF pathway led to the impairment of type H vessel formation, lower expression of osteogenic factors (including bone morphogenetic protein 2 and fibroblast growth factor 2), and decline of osteoprogenitors in the periimplant area.…”

The role of autophagy in bone homeostasis

“…In mammals, the bone is a kind of dynamic organ with a variety of essential functions, including protecting vital organs, attachment by skeletal muscle, storing mineral ions, and as an endocrine organ and an immune organ (Berger et al, 2019; Oldknow et al, 2015; Palmiter, 2017; Walsh et al, 2018). Our skeletal system undergoes a continuous remodeling cycle, carefully balances the activities of anabolic and catabolism to maintain its strength correctly and to accomplish the above tasks (Yang et al, 2020). Bone remodeling is done through the coordinated efforts of the three types of cells: bone marrow mesenchymal stem cell‐derived osteoblasts (OB) align on the bone surface and secrete bone matrix; matrix‐embedded OB further differentiate into persistent osteocytes (OCT), then the latter forms a mechanical sensing network within the bone and plays a vital role in paracrine signals; meanwhile, multinucleated osteoclasts (OC) from hematopoietic stem cells continually degrade and absorb the surrounding bone base (Abarrategi et al, 2018; Husain & Jeffries, 2017).…”