By using a mouse study, researchers from the Perelman School of Medicine at the University of Pennsylvania, have demonstrated that bone marrow adipogenic lineage precursors (MALPs) play a role in the way bones remodel themselves. Their findings suggest therapy using MALP cells to better regulate bone remodeling could result in better treatments for osteoporosis.

Their findings were published in the Journal of Clinical Investigation in a paper titled, “Bone marrow adipogenic lineage precursors (MALPs) promote osteoclastogenesis in bone remodeling and pathologic bone loss.”

The study was led by Ling Qin, PhD, an associate professor of orthopedic surgery. “Discovering new cellular and molecular mechanisms to control bone turnover will enable fine-tuning of existing therapies or design of novel therapeutics,” Qin explained. “For example, with the advance of gene-editing technology and novel cell-specific delivery approaches, in the future it would be possible to regulate MALP behavior as a therapy for bone disorders like osteoporosis.”

Osteoporosis is a bone disease that develops when bone mineral density and bone mass decreases, or when the quality or structure of bone changes. This can lead to a decrease in bone strength that can increase the risk of fractures (broken bones). Osteoporosis is a “silent” disease because you typically do not have symptoms, and you may not even know you have the disease until you break a bone.

There exists a balance between osteoblasts, which secrete the materials necessary to form new bone, and osteoclasts, which absorb old bone material to make way for new bone. A disruption in this balance can result in unhealthy bone. In osteoporosis, overactive osteoclasts eat away at bone faster than it can be reformed, resulting in bones that are less dense and more susceptible to fracture.

“Using an adipocyte-specific Adipoq-Cre to label MALPs, we demonstrated that mice with RANKL deficiency in MALPs have a drastic increase in trabecular bone mass in long bones and vertebrae starting from one month of age, while their cortical bone appears normal.
This phenotype was accompanied by diminished osteoclast number and attenuated bone
formation at the trabecular bone surface,” noted the researchers.

Qin’s group recently discovered the abundant existence of MALPs within bone. MALPs are the precursors for adipocytes that carry lipids inside bone marrow. Qin and her team showed that MALPs, but not osteoblast or osteocytes, have cell-to-cell contact with osteoclasts. Additionally, using advanced sequencing techniques at a single cell level, Qin and her colleagues found that MALPs secrete RANKL, a protein essential for forming osteoclasts, at a high level.

The researchers studied mice with RANKL deficiencies in their MALPs and observed 60–100% higher density of the spongy components of long bones. Their findings suggest that MALPs and their RANKL secretions are the main driver of osteoclast function and the absorption of existing bone.

“By identifying what appears to be the full function of MALP cells, we believe that we have uncovered an extremely promising target that would never have been considered before,” Qin said. “If their RANKL secretions can be reliably disabled, it could rebalance bone remodeling in people with osteoporosis and allow for osteoblasts and osteocytes to ‘catch up.'”

Qin’s co-author, Jaimo Ahn, MD, PhD, a former faculty member at Penn Medicine, now chief of orthopedic trauma and associate chair of orthopedic surgery at the University of Michigan added: “An exciting future step, with an eye toward clinical application, would be to target MALPs in a timed and therapeutic fashion to test how well they simultaneously decrease the bone resorption and increase bone formation.”