Abstract
Supplementation of mesenchymal stem cells (MSCs) at sites of bone resorption is required for bone homeostasis because of the non-proliferation and short lifespan properties of the osteoblasts. Calcium ions (Ca2+) are released from the bone surfaces during osteoclast-mediated bone resorption. However, how elevated extracellular Ca2+ concentrations would alter MSCs behavior in the proximal sites of bone resorption is largely unknown. In this study, we investigated the effect of extracellular Ca2+ on MSCs phenotype depending on Ca2+ concentrations. We found that the elevated extracellular Ca2+ promoted cell proliferation and matrix mineralization of MSCs. In addition, MSCs induced the expression and secretion of osteopontin (OPN), which enhanced MSCs migration under the elevated extracellular Ca2+ conditions. We developed in vitro osteoclast-mediated bone resorption conditions using mouse calvaria bone slices and demonstrated Ca2+ is released from bone resorption surfaces. We also showed that the MSCs phenotype, including cell proliferation and migration, changed when the cells were treated with a bone resorption-conditioned medium. These findings suggest that the dynamic changes in Ca2+ concentrations in the microenvironments of bone remodeling surfaces modulate MSCs phenotype and thereby contribute to bone regeneration.
Highlights
Bone is remodeled throughout adult life to regulate mineral homeostasis and to maintain the integrity and biomechanical stability of the skeleton[1]
We suggest that the ionized calcium derived from bone remodeling surface following osteoclastmediated bone resorption is an important factor underlying the supplementation of mesenchymal stem cells (MSCs) to the bone remodeling site
We showed for the first time that Ca2+ is released from bone by osteoclast-mediated bone resorption, which results in the elevation of extracellular Ca2+ concentration leading to phenotypical changes in proximal MSCs involving cell proliferation and migration (Fig. 6g)
Summary
Bone is remodeled throughout adult life to regulate mineral homeostasis and to maintain the integrity and biomechanical stability of the skeleton[1]. Bone remodeling is accomplished through tightly regulated and continuous cycles of osteoclastic and osteoblastic activity in the bone matrix[2]. This process requires osteoblast mobilization to the sites of bone reconstruction. Because osteoblasts are non-proliferative and have a short lifespan, the replenishment of osteoblasts from MSCs is required for continuous bone formation[3]. Defects in MSCs recruitment are associated with several skeletal pathologies including osteoporosis[4,5]. Stimulation of MSCs recruitment to sites of bone formation represents a promising strategy for bone regeneration
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