Abstract
We previously showed that mice with knockout of Cytl1, a functionally uncharacterized cytokine candidate, exhibit normal endochondral ossification and long-bone development. Here, we investigated the potential functions of CYTL1 in bone homeostasis. We found that Cytl1−/− mice exhibited higher bone mass than wild-type littermates and resisted ovariectomy-induced bone resorption. This led us to investigate the functions of CYTL1 in the osteogenesis and osteoclastogenesis of bone marrow-derived stem cells. CYTL1 was down-regulated during the osteogenesis of human mesenchymal stem cells (hMSCs). The osteogenesis of hMSCs was inhibited by overexpression or exogenous treatment of CYTL1, but enhanced by CYTL1 knockdown. CYTL1 decreased osteogenesis by inhibiting RUNX2 and promoted proliferation among undifferentiated hMSCs, but stimulated apoptosis among osteogenically differentiating cells. Finally, Cytl1−/− mice exhibited inhibition of osteoclast activity and the osteoclastogenesis of bone marrow-derived macrophages. Our results collectively suggest that CYTL1 negatively regulates the osteogenesis of MSCs and positively regulates osteoclastogenesis to modulate bone mass in mice.
Highlights
Cytokine-like 1 (CYTL1) was originally cloned fromCD34+ human bone marrow and cord blood as a secreted cytokine candidate[1]
We previously showed that CYTL1 regulates cartilage homeostasis without critically affecting cartilage development[8,9] and further reported that Cytl1−/− mice exhibit normal endochondral ossification and long-bone development[9]
Our results revealed that CYTL1 expression was transiently increased during the chondrogenesis of human mesenchymal stem cells (hMSCs) (Fig. 2a) but decreased during adipogenesis, wherein it remained at a low level until the late phase of differentiation (Fig. 2b)
Summary
CD34+ human bone marrow and cord blood as a secreted cytokine candidate[1]. the detailed functions of CYTL1 remain largely unknown, it exhibits structural similarities with the chemokine, CCL2, and the CCL2 receptor (CCR2) has been suggested as a potential receptor of CYTL12. Multiple molecules (e.g., growth factors and cytokines) and signaling pathways are known to regulate the activities of these lineage-specific transcription factors during BM-MSC differentiation[13,14] This differentiation plays important roles in tissue regeneration and remodeling, as bone marrow-derived osteoblasts and chondrocytes regulate the modeling/remodeling of bone and cartilage, respectively[15,16]. Given our previous finding that Cytl1−/− mice exhibited increased bone mass compared with WT littermates, we set out to investigate whether the modulation of bone mass by CYTL1 is due to alterations in the osteogenesis of MSCs and/or the osteoclastogenesis of BMMs. Here, we report in vitro results indicating that CYTL1 is downregulated during osteogenic differentiation, and that the osteogenesis of MSCs is inhibited by overexpression of CYTL1 or treatment of exogenous CYTL1 but promoted by knockdown of CYTL1. CYTL1 regulates bone mass by negatively regulating osteogenesis and positively regulating osteoclastogenesis
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