German scientists from the Albert Ludwig University of Freiburg together with their Swiss counterparts from the University of Basel, determined the main regulator of stem cells in bone regeneration. The results of the international study were published on June 18, 2018 in Proceedings of the National Academy of Sciences.
Bone tissue is a nano-composite: the mineral phase of the mature bone matrix consists of hydroxyapatite crystals. These nanocrystals, providing bone strength, are dispersed in an organic framework consisting of the protein collagen.
Despite the fact that the bone tissue rejuvenates itself throughout life, stimulating the regeneration of damaged bone is a complex process. A necessary condition in this task is the destruction of the damaged part of the bone tissue, in which molecules are released from the organic matrix, activating mesenchymal stem cells (MSCs) that reside in the bone marrow to forming a new bone.
This stage has two ways of development: MSCs can first form cartilage, which is then replaced by bone tissue (endochondral ossification); or MSCs differentiate into osteoblasts that directly repair the bone (intramembranous ossification). How the accompanying degradation of the hydroxyapatite matrix affects the choice of the type of ossification has not been known so far.
An international group of scientists, led by Professor Prasad Shastri, developed an artificial (biomimetic) mineral nanomaterial that mimics the properties of real bone. Further experiments showed that this particular component of bone is the key factor that influences its formation.
Scientists have found that the mineral phase of bone tissue stimulates the extracellular calcium-sensitive receptor (CaSR), a protein that plays a major role in the regulation of calcium homeostasis and is expressed by mesenchymal stem cells.
Stimulation of CaSR production prompted MSC to form bone, as opposed to via a cartilage step. The scientists also found that interfering with signaling via CaSR can completely shut down the formation of bone in vivo.
Also during a molecular study, they have found that stimulating parathyroid hormone-1 receptor (PTH1R), a key regulator of calcium homeostasis, helps circumvent the effect of CaSR on mesenchymal stem cells and activates endochondral ossification with an intermediate stage of cartilage formation.
“Our discovery offers new insights into how bone mineral phase can dictate new bone formation”, – says Prof. Shastri.
“The findings of our study have huge implication for designing novel implant surface for bone regeneration”, – аdds co-author Dr. Melika Sarem.
With such diseases as osteoporosis, the bone is destroyed much faster than it is restored.
“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”, – says Shastri.