Bone resorption is a fundamental part of healthy skeletal remodeling, but dysregulated osteoclast activity can cause bone loss, inflammatory joint damage, and skeletal disease. Current anti-resorptive therapies often target broad downstream mechanisms, but emerging research is revealing additional layers of regulation that could provide new opportunities for targeted interventions.
During the Tuesday, November 10, session Bad to the Bone: New Mechanisms in Bone Resorption, Katherine Motyl, PhD, Faculty Scientist, MaineHealth Institute for Research, and Tao Yang, PhD, Professor, Department of Cell Biology, Van Andel Institute, will explore two distinct but complementary pathways: epigenetic regulation within osteoclasts and neuroendocrine signaling from the nervous system. The session will take place from 10–11:30 a.m. in Room W414 of the Orange County Convention Center.
By bringing together these two perspectives, the session will highlight the increasingly interconnected pathways that may influence bone resorption and begin to answer questions about how these areas interact.
“One of these mechanisms is from the outside, one is from the inside; one is more distant from the brain to the bone, while the other is local within the osteoclast itself,” Dr. Yang said. “We tend to study these two pathways separately, but they are complementary and can inform one another for future developments.”
He will focus on epigenetic regulation of bone loss, highlighting his work with KDM5C, an X-linked epigenetic regulator. He and his research team found that loss of KDM5C increases trabecular bone mass in females but not in males.
“Sex-dependent bone mass regulation is a really important topic in the field. Previously, we considered these differences to be due to hormones, but now we’ve shifted our focus more toward what’s in our genome,” Dr. Yang said. “KDM5C is only on the X chromosome, not on the Y. How this kind of difference shapes the epigenetic landscape and the metabolism of osteoclasts makes a difference in bone resorption.”
Armed with this discovery, Dr. Yang notes that the major challenge that still exists in the field is that women are predisposed to lower bone mass over their lifetime, having a lower peak bone mass to begin with and accelerated bone loss after menopause.
“If we can find a way to preserve a higher bone mass before the menopausal stage, women will have more to burn, and because they have more, their bone can last longer,” he said.
Dr. Motyl’s talk will focus on her neuroendocrine work with beta-adrenergic signaling and its effect on bone resorption. Historically, the sympathetic nervous system’s impact on bone loss was thought to be indirect, mediated through osteoblasts recruiting osteoclasts via receptor activator of nuclear factor-kB ligand (RANKL) signaling. But her research sheds new light on this process.
“We now know that both beta 1- and beta 2-adrenergic receptors are present on osteoclasts, and that direct activation of those receptors can promote bone resorption and osteoclast differentiation,” Dr. Motyl said. “Our research has shown that these receptors may be more widely useful than originally thought.”
Dr. Motyl and her team conducted an ancillary study to a randomized controlled clinical trial investigating whether atenolol, a beta 1-selective blocker, prevents bone loss in postmenopausal women. While initial trial findings showed an early suppression of bone resorption, the protective effect waned over time.
“It leaves us with an interesting question: Was it the right choice to pick a beta 1-adrenergic receptor?” Dr. Motyl said. “A lot of my work has shown that resorption seems to be more beta 2-adrenergic receptor driven in the osteoclast.”
Moving forward, her lab aims to model why these suppressive effects wane and evaluate whether targeting beta 2-receptors could yield sustained anti-resorptive efficacy.
She will also discuss her research group’s creation and validation of Nuclei-Aware Osteoclast Instance Segmentation (NOISe), a computer-vision algorithm developed to overcome the bottleneck of manual osteoclast counting and accelerate preclinical and translational research workflows, which is freely available and published in JBMR Plus.
“We’ve collected osteoclast samples from over 50 patients, and we had hundreds of stained images to analyze. So, we worked with a computer vision expert to develop an algorithm that detects and segments out the osteoclasts in these images,” Dr. Motyl said. “It takes something that would have taken over a year’s worth of manual labor counting and turns it into a few hours’ worth of work.”
THERE’S STILL TIME TO JOIN US
If you haven’t registered for ACR Convergence 2026, you can still register on-site at the Orange County Convention Center in Orlando, Florida, through November 11. All registered participants receive on-demand access to scientific sessions through September 30, 2027.
