A research team has identified a molecule that has a crucial role in forming bone and maintaining bone health. A scientist says that it is an obvious target for new treatments for people with osteoporosis or non-healed bone fractures and for postmenopausal women with increased risk of osteoporotic fractures.
Complex and dynamic remodelling that removes old parts of bone and replaces them with new bone tissue maintains the health and strength of bones throughout life. For young people, the quantities of bone removed and replaced are about the same throughout life and the bones remain strong.
However, during menopause, women may experience accelerated bone loss in which more bone tissue is removed than replaced, resulting in decreased bone mass, increased bone fragility and development of osteoporosis, with a great risk of bone fracture.
New research shows that KIAA1199, a molecule secreted by specialised cells within the bone microenvironment – bone marrow stromal cells – is very important for the functions of osteoblasts: specialised cells within the bone that form bone.
This makes KIAA1199 an obvious target for new treatments aimed at giving people with osteoporosis healthier bones or perhaps even treatment aiming at enhancing bone healing after fractures.
“Developing treatment principles based on KIAA1199 makes sense, and the whole field of osteoporosis acutely needs to develop biological treatments that promote bone health,” explains the senior investigator of this study, Moustapha Kassem, Professor and Consultant Endocrinologist, Department of Endocrinology, Odense University Hospital and University of Southern Denmark.
The research has been published in Nature Communications.
400 molecules in the bone microenvironment
The background for the discovery was that the researchers wanted to understand which factors determine bone mass and enhance bone formation.
Bone is a very dynamic tissue that is continuously being remodelled: to remove old bone full of minor injuries and build new healthy bone, a process that occurs throughout life.
Moustapha Kassem and colleagues focus specifically on osteoblasts, the cells that build up new bones and eliminate the cells that are lazy and poorly functioning among people with osteoporosis. The group identified hormones that induce osteoblasts to produce more bone as a potential therapy for people with osteoporosis. This will also be helpful to maintain bone health among postmenopausal women with low levels of estrogen, which results in impaired bone formation.
“The activity of osteoblasts and their differentiation from stem cells are regulated through signalling molecules – hormones – in the bone microenvironment, and through our studies of the human bone microenvironment, we identified more than 400 molecules that may influence the functions of osteoblasts and affect bone health,” says Moustapha Kassem.
KIAA1199 crucial for bone formation
The researchers focused on KIAA1199, and a bioinformatics study showed that it influences cell migration and motility. This is necessary for osteoblasts since they are recruited to bone from the bone marrow. Also, a mutation in the gene encoding KIAA1199 causes a special type of hearing loss, which suggests that this signalling molecule is important in human physiology .
In their experiments with human bone tissue, the researchers showed that KIAA1199 is expressed in the bone microenvironment and when stem cells differentiate into osteoblasts. The researchers then performed stem cell experiments in which they either removed KIAA1199 from the cells or made the cells overexpress KIAA1199. Removing KIAA1199 from the stem cells induced the stem cells to differentiate into osteoblasts, whereas overexpressing KIAA1199 made this more difficult.
“This is interesting from a pharmaceutical perspective because making drugs that effectively inhibit a factor in the body is much easier than trying to get a factor produced in large quantities,” explains Moustapha Kassem.
Bones heal faster
Having studied the effect of KIAA1199 in test tubes, the researchers studied it in mice. They genetically engineered the mice to lack KIAA1199 not just in the bone microenvironment but throughout the body, and these mice developed stronger bones. Also, when the researchers induced estrogen deficiency in mice by removing their ovaries, which models the bone loss among postmenopausal women, the mice lacking KIAA1199 were protected from bone loss.
Finally, the researchers examined mice with bone fractures in mice lacking KIAA1199, and bone healing significantly improved.
“When a bone fracture takes place, osteoblasts are needed to repair the damage. They are therefore not only important for maintaining balanced bone remodelling but also for healing fractures. Our experiments showed that KIAA1199 is also important for this function of the osteoblasts,” says Moustapha Kassem.
Obvious drug target
The researchers also identified the signalling pathway by which KIAA1199 affects bone health and showed that people with osteoporosis have higher levels of KIAA1199 in their blood than healthy people of the same age. In addition, high levels of KIAA1199 in the blood increase the risk of osteoporotic bone fractures.
According to Moustapha Kassem, all this evidence indicates that KIAA1199 affects people’s bone health. This factor could therefore be a relevant target for treating or managing people who have conditions with low bone mass.
The assumption is that inhibiting KIAA1199 could increase bone formation among people with osteoporosis, enhance bone healing among people after bone fractures or prevent osteoporosis among women after menopause.
“We are currently developing antibodies that can remove KIAA1199 from the body to promote bone health, and I hope that other scientists will be interested in developing other approaches to inhibit KIAA1199 production with the aim of improving bone formation,” concludes Moustapha Kassem.
