Abstract
A negative correlation exists between the severity of osteoporosis and citrate levels in bone. Our previous research found that melatonin can significantly improve bone mass in mice with osteoporosis, but the underlying mechanism involving citrate remains unknown. Herein, we demonstrated that melatonin increased bone volume and citrate levels in ovariectomized osteoporosis mice. Melatonin increased citrate and mineralized nodules in osteoblasts induced from primary mouse bone marrow mesenchymal stem cells in vitro. ZIP-1 knockdown and overexpression confirmed that melatonin specifically upregulated ZIP-1 to rescue citrate levels and bone mass. In general, we verified that melatonin can improve bone mass by enhancing matrix mineralization, which is highly related to increased citrate secretion from osteoblasts, and that ZIP-1 is the target of melatonin. These findings reveal another role of melatonin in regulating bone remodeling and provide a research base for its possible application in the treatment of clinical osteoporosis in the future.
Highlights
The bone matrix is the largest citrate storage site in the whole body
We further found that there was a huge loss of citrate content per unit bone mass in mode animals, which could be nicely recovered with melatonin (P < 0.01) (Figure 1B)
We established a postmenopausal osteoporosis model and observed that citrate levels in osteoporotic bone decreased significantly, an imbalance occurs between osteoblasts and bone absorbing cells, and transformation of mesenchymal stem cells to osteoblasts is reduced compared with adipocytes
Summary
Citrate is an important component of the bone matrix apatite/collagen complex and provides important biomechanical properties in bone, including stability, strength, and resistance to fracture (Hu et al, 2010; Costello et al, 2014; Guo et al, 2015). Osteoblasts are specific cells that produce citrate bound to hydroxyapatite and collagen in bone that integrate into the bone matrix, and only osteogenic differentiated bone marrow mesenchymal stem cells (BMSCs) exhibit this capacity (Franklin et al, 2014). There are two properties of citrate ensuring the process of integration: a favorable spacing between COO− groups and lattice parameters in apatite, and the external-oriented CH2 groups improve its compatibility with the non-polar proline and alanine residues of collagen matrix (Hu et al, 2010).
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