A Small RNA that Increases Bone Formation in Osteoporotic Bone-Making Cells


We normally think of bone as a very static tissue that does not change very much. However bone is actually a very dynamic tissue is constantly being remodeled in response to the needs of the organism. Bone remodeling is mediated by two different types of cells: osteoblasts that build bone and osteoclasts that resorb bone. Osteoblasts are derived from mesenchymal stem cells in the stroma of the bone marrow. The differentiation of mesenchymal stem cells into osteoblasts is mediated by molecules made by bone cells when bone is damaged. Osteoclasts come from pre-osteoclast cells that are monocyte-derived cells that fuse into multinucleate osteoclasts in response to the death of osteocytes (bone cells).

In healthy bone, osteocytes secrete a molecule called sclerostin, which prevents any new bone deposition. A break in bone causes the death of osteocytes near the site of the break, and the nearby osteocytes stop secreting sclerostin and start producing growth factors, nitric oxide and prostaglandins.

Bone deposition

The lining cells of the bone marrow cavity detach and fuse with blood vessels. The mesenchymal stromal cells, under influence from IL-1, become pre-osteoblasts, and they start to secrete M-CSF, which prepares the pre-osteoclasts to fuse and become multinucleate osteoclasts. Pre-osteoclasts then express a molecule called RANKL, which binds to the RANK receptor on the surface of pre-osteoclasts and this induces them to fuse, and become mature osteoclasts. The osteoclasts secrete acid and cathepsin K to dissolve the damaged bone. The osteoclasts stop eating bone when the pre-osteoblasts mature into full-fledged osteoblasts that stop making RANKL and start making OPG, which binds to RANK, but does not activate it. Without this stimulation, the osteoclasts die. Then the osteoblasts divide, fill the cavity made by the now-deceased osteoclasts, and remake the bone. Some of the osteoblasts become entrapped in the bone matrix and become osteocytes. The bone takes several months to remineralize and 3-4 years to completely remineralize.  See here for a video of this.

Bone resorption-deposition

If there is a relative increase in bone resportion relative to bone deposition, the result is fragile, poorly mineralized bones, and this condition is known as osteoporosis. Decreased bone mass and bone strength causes an increased incidence of bone fractures, which often leads to further disability and early mortality. Bone healing is also impaired.

To treat osteoporosis, clinicians usually prescribe anti-resorptive agents that exert their effect by decreasing the rate of bone resorption. This strategy, however, has drawbacks, since as noted above, bone deposition relies on bone resorption. Inhibition of bone resorption also inhibits bone deposition, and bone tends to remain static and heal poorly.

A new paper has examined osteoporosis from the perspective of osteoblasts. It has been well established that in osteoblasts function is diminished in osteoporotic patients. Therefore increase osteoblast function is of chief interest. Work from the laboratories of Jihua Chen and Yan Jin from the Fourth Medical University has shown that a miniature RNA molecule called miR-26a plays a critical role in modulating bone formation during osteoporosis. Chen and Jin and others discovered that miR-26a treatment of mesenchymal stem cells effectively improved the osteogenic differentiation capability of these mesenchymal stem cells. In these experiments, they isolated mesenchymal stem cells from female mice that had their ovaries removed. Such mice are prone to undergo osteoporosis because they lack the hormone estrogen that stimulates osteoblast function. When these stem cells were treated with MiR-26a, they increased their bone-making capacities by in culture and when injected into live mice.

Further work showed that MiR-26a directly targets a gene called Tob1. Tob1 negatively regulates the BMP/Smad signaling pathway, and MiR-26a binds to the rear mRNA (3′-untranslated region) of Tob1, and prevents Tob1 translation.

These findings indicate that miR-26a is a potentially promising therapeutic candidate to enhance bone formation in order to treat osteoporosis and to promote bone regeneration in osteoporotic fracture healing.

For the article, go here.

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Published by

mburatov

Professor of Biochemistry at Spring Arbor University (SAU) in Spring Arbor, MI. Have been at SAU since 1999. Author of The Stem Cell Epistles. Before that I was a postdoctoral research fellow at the University of Pennsylvania in Philadelphia, PA (1997-1999), and Sussex University, Falmer, UK (1994-1997). I studied Cell and Developmental Biology at UC Irvine (PhD 1994), and Microbiology at UC Davis (MA 1986, BS 1984).