Formation of joints in the developing embryo and their maintenance after birth is sensitive to mechanical movement. Now, researchers at Indian Institute of Technology (IIT) Kanpur have deciphered the molecular mechanism underlying this phenomenon. They have demonstrated how permanent cartilage is formed in an embryo due to mechanical movement. They also found out how permanent cartilage is lost and temporary or transient cartilage is formed in its place in the absence of movement.
While permanent cartilage lines the joint, the transient cartilage is a bone-forming one. Earlier this group demonstrated that during embryonic development, a bipotential cartilage population gives rise to both permanent and transient cartilage. BMP and Wnt are two major signals regulating this process. While BMP promotes transient cartilage formation, Wnt promotes permanent cartilage formation.
In patients with osteoarthritis, the permanent cartilage acquires all the characteristics of a temporary cartilage, which affects joint function. Currently, in people with osteoarthritis, it is not possible to reverse the fate of permanent cartilage that has become a temporary-like cartilage. The work done by a team led by Prof. Amitabha Bandyopadhyay from the Department of Biological Sciences and Bioengineering at IIT Kanpur suggests that it might be possible to prevent osteoarthritis from worsening if intervened at an early stage. The results were published in the journal Development. The work was carried out in collaboration with the laboratory of Prof. Paula Murphy of Trinity College Dublin.
Transient cartilage
BMP signalling — which helps in the formation of transient cartilage — is normally not present in permanent cartilage cells in a joint. That transient cartilage forms in the place of permanent cartilage due to joint immobilisation was already known. And independently, the team had shown that BMP signalling promotes transient cartilage formation. “So we wanted to find out if immobilising the joints in a chick embryo allows the BMP signalling to come up in the joint cartilage cells. We did find that happening,” Prof. Bandyopadhyay says.
The investigation into what causes the BMP signalling to be present in future permanent cartilage cells when the joint is immobilised led them to a surprise finding. The lead author, Pratik Singh, found out that an inhibitor of BMP signalling (Smurf1) is absent in the joint that is immobilised resulting in increased BMP signalling. “The role of the Smurf1 inhibitor is to maintain a BMP-free area thereby enabling the progenitor cells to become permanent cartilage. But due to increased BMP signalling the permanent cartilage gets converted into transient-like cartilage,” says Prof. Bandyopadhyay.
The Smurf1 inhibitor is not directly involved in joint cartilage formation but creates an environment that permits the formation of permanent cartilage by keeping the BMP signalling under check.
Toggle switch
Mechanical movement seems to act like a toggle switch. In the presence of it, Wnt – the signal that promotes joint cartilage – is on and BMP signalling is off in the joint cartilage cells. The opposite is true when the joint is immobilized. This is the reason why immobilisation of joints causes greater disturbance to permanent cartilage than even inhibition of Wnt signalling. “We are now investigating if osteoarthritis is also associated with appearance of BMP signalling in the wrong place. If so, we can block the BMP signalling in these cells during the early-stage of osteoarthritis to possibly prevent the condition from worsening,” he says.
