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New Treatment of Osteoporosis Through a Potential Therapeutic Target

Researchers from the Perelman School of Medicine at the University of Pennsylvania have conducted a study using a mouse sample. They found that bone marrow adipogenic lineage precursors (MALPs) play a role in the reshaping of bones. Their results indicate that therapy using MALP cells to help control bone remodelling could lead to better osteoporosis treatments.

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

Ling Qin, PhD, an associate professor of orthopaedic surgery, led the research. He explained "The discovery of new cellular and molecular mechanisms to control bone turnover will allow current therapies to be fine-tuned or novel therapeutics designed," Qin  further explained. "For example, it would be possible to regulate MALP behaviour as a therapy for bone disorders such as osteoporosis in the future with the advancement of gene-editing technology and novel cell-specific delivery approaches."

Osteoporosis is a disorder of the bone that occurs when the density of bone minerals and bone mass decreases, or when bone content or structure changes. This can result in a reduction in the strength of the bone that can increase the likelihood of fractures (broken bones). Osteoporosis is a "silent disease because you usually have no symptoms, and when you break a bone, you do not even know you have the disease.

There is a compromise between osteoblasts that secrete new bone-forming materials and osteoclasts that absorb old bone content to give way to new bone. Unhealthy bones may result in a disturbance of this equilibrium. Overactive osteoclasts chew away at the bone more easily in osteoporosis than they can reform, resulting in bones that are less dense and more vulnerable to fracture.

he said, "We have shown that mice with RANKL deficiency in MALPs have a dramatic increase in trabecular bone mass in long bones and vertebrae beginning at one month of age, using an adipocyte-specific Adipoq-Cre to mark MALPs while their cortical bone appears normal. This phenotype was followed by a decreased amount of osteoclast and attenuated bone Shape at the surface of the trabecular bone,"

The abundant presence of MALPs inside the bone was recently discovered by Qin's party. The precursors for adipocytes bearing lipids within the bone marrow are MALPs. Qin and her team demonstrated that MALPs have cell-to-cell interaction with osteoclasts, but not osteoblasts or osteocytes. In addition, Qin and her colleagues found that MALPs secrete RANKL, a protein important for forming osteoclasts, at a high level, using advanced sequencing techniques at a single cell level.

In their MALPs, the researchers researched mice with RANKL deficiencies and found a 60-100 percent greater density of long bone spongy components. Their results indicate that the main driver of osteoclast activity and the absorption of existing bone is MALPs and their RANKL secretions.

"We believe that we have uncovered an extremely promising target that would never have been considered before by identifying what appears to be the full function of MALP cells," Qin said. "If it is possible to reliably disable their RANKL secretions, it could rebalance bone remodelling in osteoporosis individuals and allow osteoblasts and osteocytes to 'catch up.'"

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

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