Osteoclasts And Their Extracellular Vesicles In Craniofacial Bone Regeneration

Bone remodeling is a tightly coupled process between bone-forming osteoblasts (OBs) and bone-resorbing osteoclasts (OCs) to maintain Craniofacial bone. However, the mechanisms responsible for the coupling between OCs and OBs have not been fully elucidated. We delved into the bone healing process through immunohistochemical staining. We examined how osteoclasts influence the osteogenic differentiation of MSCs using a co-culture method in vitro. Additionally, we evaluated bone regeneration potential in vivo by utilizing bone defect models. To better understand the intricate interactions between OBs and OCs, we employed proteomic and functional analysis techniques to uncover the underlying mechanisms. We first observed that osteoclasts proceed earlier than bone formation by osteoblasts in the bone healing process, and osteoclasts display a species-independent stimulation of osteogenic differentiation on MSCs. We further validated that extracellular vesicles by osteoclasts (OC-EVs) mainly contributed to this process and demonstrated the efficacy of OC-EVs in treating mandibular bone defects. It is further revealed that mature osteoclasts secrete thrombin-cleaved phosphoprotein 1 (SPP1) through extracellular vesicles which triggers MSCs osteogenic differentiation into OBs by activating TGFβ1 and SMAD3 signaling. Osteoclasts play underappreciated roles in bone regeneration, primarily through their extracellular vesicles. This biological mechanism suggests a paradigm shift in our understanding of osteoclast function and signaling, offering new therapeutic perspectives for skeletal disorders requiring bone formation.