Muscle cells play a vital role in repairing broken bones

Bone healing is a complex process that relies on the coordinated activity of many different cell types. While it is known that bone-forming cells called osteoblasts are able to rebuild damaged tissue, researchers are increasingly finding that some extraskeletal cells remain dormant under normal conditions but can acquire bone-forming functions after injury. Given the diversity of cell populations in the musculoskeletal system, the precise role of individual cell types remains unexplored.

Against this background, a study was published online in Volume 14 of the journal Orthopedic research Jul 06, 2026 revealed an unexpected role for muscle-resident fibroblast precursors (FAPs), along with a smaller number of superficial periosteal cells, in the repair of fractured bone. The study was supervised by Dr. Ugur M. Ayturk and colleagues from the US Skeletal Health and Orthopedics Research Program.

FAPs are found in skeletal muscle, while superficial periosteal cells are found in the thin connective tissue called the periosteum, which covers the outside of bones. Although these cells normally remain inactive, they are recruited after injury to help repair broken bones.

Our findings show that extraskeletal cells, especially FAPs, are recruited to help repair bone fractures and may represent a promising therapeutic target to promote fracture healing.

D. Ugur M. Ayturk, Skeletal Health and Orthopedics Research Program, USA

To study these cells, the researchers found Clec3b expression as a highly specific marker for these normally dormant progenitor cells. They designed a mouse model in which they labeled cells expressing Clec3b with a fluorescent marker, allowing them to track their location under normal conditions and their response after infection.

During normal bone development, they found that these cells remained in the muscle and superficial periosteum and never migrated to the bone or differentiated into osteocytes. However, after bone fractures, these cells quickly migrate to the site of injury, where many differentiate into osteocytes that produce new bone and aid in the healing process. Within three weeks, the researchers found that about 28% of the bone cells in the healing callus arose from Clec3b lineage cells. Some of these cells also became bone marrow stromal cells, helping to rebuild the supportive environment within the bone. Notably, the cells stopped expressing Clec3b during their differentiation, suggesting that the mark is associated with their dormant progenitor state.

Single-cell RNA sequencing confirmed this transformation, showing that dormant Clec3b lineage cells gave rise to new populations with the molecular characteristics of bone marrow stromal cells and post-fracture osteoblasts.

Furthermore, researchers investigated the origin of these bone-forming cells. Although similar cells were also found in the periosteum, their experiments showed that skeletal muscle was the main source. Even after the periosteum was surgically removed before injury, Clec3b-positive cells still reached the fracture site and developed into osteogenic cells. Bone grafts that included surrounding muscle produced significantly more osteogenic cells of the Clec3b lineage than grafts that did not contain muscle, suggesting that skeletal muscle is the main source of these regenerative cells.

The cells were also found to contribute to heterotopic ossification, a condition in which bone forms in muscles and other soft tissues after injury. In mouse models, Clec3b lineage cells differentiate into chondrocytes and osteoblasts, becoming a major source of this abnormal bone. “When we blocked the main pathway required for bone formation or depleted these cells, fracture healing and abnormal bone growth were significantly reduced. This discovery highlights their important role in both processes,” says Dr. Ayturk.

The researchers believe that these cells could become promising therapeutic targets. Activating them may promote fracture healing, while reducing bone formation activity can help prevent unwanted bone growth after serious injuries.