Research identifies how master regulator, bone-building protein can be used for therapy

June 21, 2017, Baylor College of Medicine

The WNT1 ligand has previously been identified in bone disease, but its role in bone homeostasis, its cellular source and targets in bone have only just recently been identified. The research, led by Dr. Brendan Lee at Baylor College of Medicine, appears in the Journal of Clinical Investigation.

To determine the bone-specific function of WNT1, the mutation that has been associated with recessive forms of Osteogenesis Imperfecta (OI) and other forms of early-onset osteoporosis, Lee, chair of the Department of Molecular and Human Genetics at Baylor, generated mouse models to study the consequences of both the loss and gain of WNT1 function in a specialized called the osteocyte.

"This research builds on previous work that identified WNT1's role in coordination and its known effect on brain development. Now, we understand how this molecule works in bone, and this paper tells us that WNT1 is produced by osteocytes to control the activity of the bone-forming cell, the osteoblast," said Lee, also the Robert and Janice McNair Endowed Chair and professor of molecular and at Baylor.

The role of osteocytes, blasts and clasts

The over- or underexpression of WNT1 is controlled by osteocytes, or bone embedded cells. The osteocytes produce WNT1 to signal to bone-forming cells called osteoblasts that reside on the surface of bone via a biochemical pathway called mTORC1. When WNT1 is overexpressed by the osteocyte, is stimulated due to an increase in osteoblast numbers and collagen production following the activation of the mTORC1 pathway in these cells.

"Osteocytes are embedded in the bone, with osteoblasts and osteoclasts sitting on the surface adding or removing bone, respectively," explained Lee. "It turns out, osteocytes are actually the master controllers of this balance of bone formation and resorption in part by acting as either a receiver or sender of WNT signals."

"We knew previously from others' work that osteocytes could inhibit bone formation by producing the protein sclerostin, which represses osteoblast function. This research brings the cycle of information full circle by showing that while sclerostin turns the osteoblasts off, WNT1 from osteocytes turns them on," Lee said.

On the other hand, loss of WNT1 function resulted in low bone mass and spontaneous fracturing, similar to that seen in patients with OI. In this case, the osteocyte is not producing WNT1. However, osteocytes also can receive WNT signals themselves, leading them to control the activity of bone-removing cells, the osteoclasts.

Therapeutic impact

Primary therapies traditionally used to treat OI have shown limited efficacy in combating WNT1-related OI and osteoporosis. However, Lee and his research team identified anti-sclerostin antibody (Scl-Ab) treatment is effective in augmenting the action of other WNT ligands to improve bone mass and to significantly decrease the number of fractures in swaying mice, a model of WNT1 related OI and osteoporosis.

"The results of this study, while conducted in mice, have important implications for the treatment of OI and osteoporosis in humans down the road," Lee said. "By blocking sclerostin, the can be repaired effectively in diseases related to loss of WNT1 suggesting a personalized therapy. This is exciting especially as a promising anti-sclerostin drug is already in clinical development."

Explore further: Weight-bearing exercises promote bone formation in men

More information: Frank Rauch. The brains of the bones: how osteocytes use WNT1 to control bone formation, Journal of Clinical Investigation (2017). DOI: 10.1172/JCI95386

Related Stories

Weight-bearing exercises promote bone formation in men

March 22, 2017
Osteoporosis affects more than 200 million people worldwide and is a serious public health concern, according to the National Osteoporosis Foundation. Now, Pamela Hinton, associate professor in the Department of Nutrition ...

Study shows how atherosclerosis and osteoporosis are linked

May 6, 2016
Patients with atherosclerosis—the buildup of cholesterol and fat in arteries—are at a higher risk of osteoporosis. A new study published in the American Journal of Physiology—Endocrinology and Metabolism shows how the ...

Non-coding RNA molecule could play a role in osteoporosis

March 28, 2017
Researchers from Hong Kong Baptist University and colleagues have demonstrated that a molecule called miR-214-3p plays a role in inhibiting bone formation. MiR-214-3p is a microRNA (miRNA): a non-coding RNA involved in regulating ...

Identification of a molecule linking bone loss and bone formation

August 1, 2013
Bone integrity requires skeletal remodeling, which involves both bone formation and resorption. It has been previously shown that the formation of new bone is triggered by degradation of older bone. However, it is unknown ...

Even minor physical activity may benefit bone health in premenopausal women

August 15, 2012
A study to be published in the Endocrine Society's Journal of Clinical Endocrinology and Metabolism (JCEM) suggests that physical activity for premenopausal women is very effective in reducing sclerostin—a known inhibitor ...

Signaling pathway could be key to improved osteoporosis treatment

October 19, 2016
A molecular signaling pathway identified by an international research team could be the basis of improved treatment for osteoporosis. In their report published in the online journal Nature Communications, the investigators ...

Recommended for you

Spare parts from small parts: Novel scaffolds to grow muscle

February 20, 2018
Australian biomedical engineers have successfully produced a 3D material that mimics nature to transform cells into muscle.

Clues to obesity's roots found in brain's quality control process

February 20, 2018
Deep in the middle of our heads lies a tiny nub of nerve cells that play a key role in how hungry we feel, how much we eat, and how much weight we gain.

Study looks at how newly discovered gene helps grow blood vessels

February 19, 2018
A new study published today found that a newly discovered gene helps grow blood vessels when it senses inadequate blood flow to tissues.

Scientists produce human intestinal lining that re-creates living tissue inside organ-chip

February 16, 2018
Investigators have demonstrated how cells of a human intestinal lining created outside an individual's body mirror living tissue when placed inside microengineered Intestine-Chips, opening the door to personalized testing ...

Data wave hits health care

February 16, 2018
Technology used by Facebook, Google and Amazon to turn spoken language into text, recognize faces and target advertising could help doctors fight one of the deadliest infections in American hospitals.

Researcher explains how statistics, neuroscience improve anesthesiology

February 16, 2018
It's intuitive that anesthesia operates in the brain, but the standard protocol among anesthesiologists when monitoring and dosing patients during surgery is to rely on indirect signs of arousal like movement, and changes ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.