Abstract
Using femur explants from mice as an in vitro model, we investigated the effect of the physiological polymer, inorganic polyphosphate (polyP), on differentiation of the cells of the bone marrow in their natural microenvironment into the osteogenic and chondrogenic lineages. In the form of amorphous Ca-polyP nano/microparticles, polyP retains its function to act as both an intra- and extracellular metabolic fuel and a stimulus eliciting morphogenetic signals. The method for synthesis of the nano/microparticles with the polyanionic polyP also allowed the fabrication of hybrid particles with the bisphosphonate zoledronic acid, a drug used in therapy of bone metastases in cancer patients. The results revealed that the amorphous Ca-polyP particles promote the growth/viability of mesenchymal stem cells, as well as the osteogenic and chondrogenic differentiation of the bone marrow cells in rat femur explants, as revealed by an upregulation of the expression of the transcription factors SOX9 (differentiation towards osteoblasts) and RUNX2 (chondrocyte differentiation). In parallel to this bone anabolic effect, incubation of the femur explants with these particles significantly reduced the expression of the gene encoding the osteoclast bone-catabolic enzyme, cathepsin-K, while the expression of the tartrate-resistant acid phosphatase remained unaffected. The gene expression data were supported by the finding of an increased mineralization of the cells in the femur explants in response to the Ca-polyP particles. Finally, we show that the hybrid particles of polyP complexed with zoledronic acid exhibit both the cytotoxic effect of the bisphosphonate and the morphogenetic and mineralization inducing activity of polyP. Our results suggest that the Ca-polyP nano/microparticles are not only a promising scaffold material for repairing long bone osteo-articular damages but can also be applied, as a hybrid with zoledronic acid, as a drug delivery system for treatment of bone metastases. The polyP particles are highlighted as genuine, smart, bioinspired nano/micro biomaterials.
Highlights
Cells can self-renew and/or produce differentiated cells basically through the following two ways: first, by proliferation of stem cells producing differentiated cells, by de- and subsequently by re-differentiation or by trans-differentiation, or second, by proliferation of pluripotent progenitor cells producing differentiated progeny cells or by different lineage-restricted progenitor cells each of them producing different differentiated cells [1]
Using femur explants from mice as an in vitro model, we investigated the effect of the physiological polymer, inorganic polyphosphate, on differentiation of the cells of the bone marrow in their natural microenvironment into the osteogenic and chondrogenic lineages
The results revealed that the amorphous Ca-polyP particles promote the growth/viability of mesenchymal stem cells, as well as the osteogenic and chondrogenic differentiation of the bone marrow cells in rat femur explants, as revealed by an upregulation of the expression of the transcription factors SOX9 and RUNX2
Summary
Cells can self-renew and/or produce differentiated cells basically through the following two ways: first, by proliferation of stem cells producing differentiated cells, by de- and subsequently by re-differentiation or by trans-differentiation, or second, by proliferation of pluripotent progenitor cells producing differentiated progeny cells or by different lineage-restricted progenitor cells each of them producing different differentiated cells [1]. The cellular constituents of bone are osteoblasts (forming the bone material), osteocytes (present within the mature bone tissue and living as long as the organism itself), osteoclasts (degrading bone), and lining cells (involved in coupling bone resorption to bone formation), while the cells in cartilage comprise chondroblasts (perichondrial cells which develop to chondrocytes) and chondrocytes (producing and maintaining the cartilaginous matrix) [2] Both cell lineages originate from osteochondro-progenitor cells, which arise from mesenchymal stem cells (MSC) in the bone marrow and differentiate into osteoblasts or chondrocytes, depending on the signaling molecules they are exposed to [3]. Due to the inherent potential of MSCs to differentiate either into bone, cartilage, or fat tissue, recent studies have shown their healing capability by improving angiogenesis and preventing fibrosis [4] They exhibit a positive role in tissue repair and tissue regeneration, especially in the field of bone-healing problems and early stages of local bone defects, as well as osteo-articular diseases [5]. It is the physiological polymer polyphosphate (polyP) that induces the repair processes of both bone and cartilage in an anabolic way
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