From The Labs

There is a new player in adult bone healing

Adult bone repair relies on the activation of bone stem cells, which still remain poorly characterized. Bone stem cells have been found both in the bone marrow and in the outer layer of tissue, called periosteum, that envelopes the bone. Of the two, periosteal stem cells are the least understood.

When bone cells called osteocytes, like the one in this image, sense mechanical stress on the skeleton due to activities such as weight-lifting or even walking, they transform the forces into biological responses, which signal other cells to make or remove bone. Image courtesy of the National Institute of Arthritis and Musculoskeletal and Skin Diseases/NIH

Having a better understanding of how adult bones heal could reveal new ways of repair fractures faster and help find novel treatments for osteoporosis.  Dr. Dongsu Park and his colleagues at Baylor College of Medicine investigate adult bone healing and recently uncovered a new mechanism that has potential therapeutic applications.

Dr. Dongsu Park

“Previous studies have shown that bone marrow and periosteal stem cells, although they share many characteristics, also have unique functions and specific regulatory mechanisms,” said Park, who is assistant professor of molecular and human genetics and of pathology and immunology at Baylor.

It is known that these two types of bone stem cells comprise a heterogeneous population that can contribute to bone thickness, shaping and fracture repair, but scientists had not been able to distinguish between different subtypes of bone stem cells and study how their different functions are regulated.

In the current study, Park and his colleagues developed a method to identify different subpopulations of periosteal stem cells, define their contribution to bone fracture repair in live mouse models and identify specific factors that regulate their migration and proliferation under physiological conditions.

Periosteal stem cells are major contributors to bone healing

The researchers discovered specific markers for periosteal stem cells in mice. The markers identified a distinct subset of stem cells that showed to be a part of life-long adult bone regeneration.

“We also found that periosteal stem cells respond to mechanical injury by engaging in bone healing,” Park said. “They are important for healing bone fractures in the adult mice and, interestingly, they contribute more to bone regeneration than bone marrow stem cells do.”

In addition, the researchers found that periosteal stem cells also respond to inflammatory molecules called chemokines, which are usually produced during bone injury. In particular, they responded to chemokine CCL5.

Adult periosteum maintains genetically distinct stem cell subsets with a CCL5-dependent migratory mechanism required for bone maintenance and injury repair. Cell Stem Cell/Park lab

Periosteal stem cells have receptors – molecules on their cell surface called CCR5 – that bind to CCL5, which sends a signal to the cells to migrate toward the injured bone and repair it. Deleting the CCL5 or the CCR5 gene in mouse models resulted in marked defects or delayed healing.  When the researchers supplied CCL5 to CCL5-deficient mice, bone healing was accelerated.

The findings suggested potential therapeutic applications. For instance, in individuals with diabetes or osteoporosis in which bone healing is slow and may lead to other complications resulting from limited mobility, accelerating bone healing may reduce hospital stay and improve prognosis.

“Our findings contribute to a better understanding of how adult bones heal. We think this is one of the first studies to show that bone stem cells are heterogeneous, and that different subtypes have unique properties regulated by specific mechanisms,” Park said. “We have identified markers that enable us to tell bone stem cell subtypes apart and study what each subtype contributes to bone health. Understanding how bone stem cell functions are regulated offers the possibility to develop novel therapeutic strategies to treat adult bone injuries.”

Find all the details of this study in the journal journal Cell Stem Cell.

Other contributors to this work include Laura C. Ortinau, Hamilton Wang, Kevin Lei, Lorenzo Deveza, Youngjae Jeong, Yannis Hara, Ingo Grafe, Scott Rosenfeld, Dongjun Lee, Brendan Lee and David T. Scadden. The authors are affiliated with one of the following institutions: Baylor College of Medicine, Texas Children’s Hospital, Pusan National University School of Medicine and Harvard University.

This study was supported by the Bone Disease Program of Texas Award and The Caroline Wiess Law Fund Award, the NIAMS of the National Institutes of Health under award numbers 1K01AR061434 and 1R01AR072018 and U54 AR068069 and the NIDDK of the NIH.


By Ana María Rodríguez, Ph.D.


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