Bone regeneration mystery solved
False-colour SEM image of a biomimetic bone-like mineral phase (green) amongst a matrix deposited by mesenchymal stem cells (purple).
Researchers from the University of Freiburg and the University of Basel have finally identified exactly how bone's mineral phase influences tissue regeneration.
As part of the discovery, Professor Prasad Shastri from the Institute for Macromolecular Chemistry at Freiburg, and colleagues, used a novel biomimetic bone-like mineral phase - as shown in a stunning SEM image - to understand the regeneration processes, with huge implications for bone implant design.
While bone tissue continually rejuvenates, the destruction of unhealthy bone is a necessary step in this process of new bone formation.
Bone comprises a hydroxyapatite mineral phase, offering bone stability, dispersed amongst a protein collagen matrix.
During bone destruction, biomolecules in this collagen matrix are released in order to coax mesenchymal stem cells (MSCs) within bone marrow to actively form bone.
However, at this point of bone regeneration, the stem cells either become bone cells and deposit bone, or become cartilage cells and deposit a cartilage matrix that is later transformed into bone.
Researchers have long known that the accompanying degradation of the hydroxyapatite mineral phase matrix affects this crossroad, but haven't pinpointed in what way.
With this in mind, researchers used a biomimetic bone-like mineral phase, developed in the Shastri laboratory, to investigate the impact of bone mineral phase on the stem cell's pathway choice.
Analysing an interface between this bone-like mineral phase and a collagen matrix, the researchers discovered that the mineral phase of bone can stimulate a receptor called extracellular calcium sensing receptor (CaSR), a protein that senses calcium outside the cells and is expressed by the stem cells.
Over-stimulation of CaSR forces the stem cells to directly form bone as opposed to via a cartilage step.
The researchers also discovered that interfering with signaling via CaSR can completely shut down the formation of bone in vivo.
And they also found that stimulating a parathyroid hormone-1 receptor, the key regulator of calcium ion homeostasis, can rescue the stem cells from the clutches of CaSR and promote the formation of bone via a cartilage intermediate.
“Our discovery offers new insights into how bone mineral phase can dictate new bone formation,” says Shastri. “Our study places CaSR squarely at the middle of the bone regeneration paradigm and we can now say that it is a master regulator of bone formation and this might explain why osteoporotic patients have a hard time healing their fractures.”
"Our findings have a huge implication for designing novel implant surface for bone regeneration,” adds Shastri's colleague, Dr Melika Sarem.
Research is published in PNAS.