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Hydrostatic Pressure Mimics Walking to Result in Formation of Cartilage

December 1, 2017
Researchers presented a methodology for stimulating new tissue formation based on cyclical hydrostatic pressure, perhaps leading to cartilage regeneration as a means to restore joint health.

With Elizabeth Loboa, PhD, and Mark A. Young, MD, MBA, FACP

An increase in cartilage tissue formation occurred under cyclic hydrostatic pressure, but not with simulated microgravity in in vitro human adipose-derived stem cells (hASC), according to results published in Aerospace Medicine and Human Performance.1 Understanding chondrogenesis is an important feature in joint pain care as cartilage does not regenerate in the human body.

Previous research on chondrogenesis used bioreactors--either hydrostatic pressure or microgravity--to assess formation of cartilage, but these experiments relied on either hydrostatic pressure or microgravity independently.2-4 This study is the first to directly compare the effects of hydrostatic pressure and microgravity on chondrogenesis in hASC.1

Walking may be sufficient to initiate development of cartilage.

Clearer Understanding of Mechanical Loading

We hypothesized that mimicking the mechanical load experienced by walking in normal gravity via cyclic hydrostatic pressure would result in differentiation of cartilage and that the mimicked removal of gravity may lead to less chondrogenesis, said senior author, Elizabeth Loboa, PhD, dean of the College of Engineering and professor of bioengineering at the University of Missouri.

“These results did not surprise us as the findings are right along the lines of what we were anticipating at the outset of this study,” said Dr. Loboa told Practical Pain Management, “Since my work in the field of differentiation and regeneration of musculoskeletal tissues has focused on the critical role of biomimetic mechanical loading on differentiating stem cells to create new tissues. I have been somewhat intrigued that there had been studies showing that no mechanical load would be good for musculoskeletal tissue formation because frankly, it’s very counter-intuitive and inconsistent with what I know the mechanical environment is in vivo.”

Dr. Loboa and her researcher team cultured pellets of hASC for 14 days in simulated microgravity with a rotating wall vessel, under cyclic hydrostatic pressure (7.5 MPa, 1 Hz, 4 h d-1) with a hydrostatic pressure vessel, or in controlled conditions in an incubator.1

Influence of Hydrostatic Pressure on Genetic Expression of Cartilage

Compared to cyclin microgravity, cyclic hydrostatic pressure increased the expression of three genes: Aggrecan, Sox9, and Collagen II.1  Aggrecan, also known as cartilage-specific proteoglycan core protein or chondroitin sulfate proteoglycan 1, coded for a protein that is a critical component the extracellular matrix of cartilage. Sox9 codes for a transcription factor that function in the differentiation of cartilage, among other traits. Collagen II encodes a gene for a protein in both articular and hyaline collagen.

Since gene expression may vary and be quite sensitive to circadian rhythms, these researchers examined correlated phenotypes beyond gene expression.1

“We didn’t look solely at gene expression because gene expression is not enough. You really do need to take it further,” said Dr. Loboa.

Cyclic hydrostatic pressure also increased the production of the protein sulfated glycosaminoglycan threefold compared to microgravity.1 Sulfated glycosaminoglycan forms an important part of the extracellular matrix in soft tissues such as cartilage. Additionally, hydrostatic pressure resulted in stronger intensity of vimentin staining and better organization in comparison to microgravity.

Vimentin Appears Central to Chondrogenesis    

“We were trying to understand the processes in the cells, cytoskeleton, and the nucleus as transduce mechanical loads have always been fascinating to me as there’s no deformation with hydrostatic pressure. Vimentin has been shown to regulate chondrogenesis so that seeing this increase in vimentin staining intensity is worthy of greater attention. To think that vimentin might be the factor that is regulating cyclic hydrostatic pressure signal transduction is very exciting,” Dr. Loboa said.

Finally, patterns of Wnt signaling in microgravity were changed so as to suggest decreased chondrogenesis in microgravity compared to hydrostatic pressure,1 according to the researchers.

“We need to apply this finding in vivo since we have tried to simulate in vitro as close to a real-life environment as possible, and we have analyzed these experiments as best we could. The goal now is to look at these signaling pathways and do some knock-downs in mice. I am also interested in examining whether we can induce chondrogenesis pharmacologically after removing all the loading,” she said.

These results suggest that cyclic hydrostatic pressure promotes chondrogenic differentiation of hASC. Additionally, simulated microgravity might inhibit chondrogenesis, likely due to the lack of mechanical loading.1 Ultimately, these results create even more questions and considerations.

“At the end of the day, what we want to do is help patients here on earth in an unloaded environment and astronauts who might experience a fracture, especially as we consider longer missions,"  said Dr. Loboa, "Can we pharmacologically induce hydrostatic pressure? Can we overcome the problems of not having mechanical loading by having some potential regulation of a signaling pathway? Or, is there something we might create like a human bioreactor if a patient has a fracture or there’s a problem with the cartilage generation? Could we send this into space with astronauts?” she said when considering where to take their work from here.

Clinical Relevance of the Findings

"This study presents sound basic science, and the findings are intriguing from the standpoint of pain management but it is still very early," said  Mark A. Young, MD, MBA, FACP, chairman of the department of physical medicine and rehabilitation at the Maryland Rehabilitation Center in White Marsh, Maryland.

"Every now and then, science delivers fundamental cures and advances in pain medicine, and based on these findings, there is potential for this to become a landmark study with translational value down the road," Dr. Young told Practical Pain Management, "I can imagine the potential for breakthroughs for many musculoskeletal conditions that may come from this study."

Dr. Loboa and Dr. Young have no financial conflicts of interest.

Last updated on: December 4, 2017
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