Bone healing is a complex process that depends on the coordinated activity of many different cell types. While bone-forming cells called osteoblasts are known to rebuild damaged tissue, researchers have increasingly found that some cells outside the skeleton remain dormant under normal conditions but can\u00a0acquire\u00a0bone-forming functions after injury.\u00a0Given the diversity of cell populations in the musculoskeletal system, the\u00a0precise role of individual cell types\u00a0remain\u00a0unexplored.\u00a0<\/p>\n
Against this backdrop, a\u00a0study published\u00a0online\u00a0in\u00a0Volume 14 of the journal\u00a0Bone Research\u00a0on July 06, 2026,\u00a0revealed\u00a0an unexpected role\u00a0of\u00a0muscle-resident\u00a0fibroadipogenic\u00a0progenitors (FAPs), together with a smaller population of superficial periosteal cells, in repairing\u00a0fractured\u00a0bones.\u00a0The study was led by Dr. Ugur\u00a0M.\u00a0Ayturk and colleagues from\u00a0the\u00a0Skeletal Health and Orthopedic Research Program, USA.\u00a0<\/p>\n
FAPs\u00a0reside\u00a0in skeletal muscle, while superficial periosteal cells are found in the thin connective tissue\u00a0called periosteum,\u00a0covering the outer surface of bones. Although these cells normally\u00a0remain\u00a0inactive, they are recruited following injury to help repair\u00a0fractured\u00a0bones.\u00a0<\/p>\n
\nOur\u00a0findings show that extra-skeletal cells, particularly FAPs, are recruited to help repair bone fractures and could represent a promising therapeutic target to enhance fracture healing.”\u00a0<\/p>\n
Dr. Ugur M. Ayturk, Skeletal Health and Orthopedic Research Program, USA<\/p>\n<\/blockquote>\n
To study these cells, the researchers\u00a0found\u00a0Clec3b\u00a0expression\u00a0as a highly specific marker for these normally dormant progenitor cells. They engineered a mouse model in which they labelled cells expressing\u00a0Clec3b\u00a0with a fluorescent tag, allowing them to track their location under normal conditions and their response after injury.\u00a0<\/p>\n
During normal bone growth, they found that these cells remained in muscle and the superficial\u00a0periosteum\u00a0and\u00a0they\u00a0never migrated into bone or differentiated into osteoblasts.\u00a0Following bone fractures, however, these cells rapidly migrated to the injury site, where many\u00a0differentiated into osteoblasts that produced new\u00a0bone\u00a0and\u00a0aiding\u00a0in\u00a0healing\u00a0process. Within three weeks, the researchers found that about 28% of the osteoblasts in the healing callus originated from\u00a0Clec3b-lineage cells. Some of these cells also became bone marrow stromal cells, which helped rebuild the supportive environment inside the bone. Notably, the cells stopped expressing\u00a0Clec3b\u00a0as they differentiated,\u00a0indicating\u00a0that the marker is associated with their dormant progenitor state.\u00a0<\/p>\n
Single-cell RNA sequencing confirmed this transition, showing that dormant\u00a0Clec3b-lineage cells gave rise to new populations with the molecular characteristics of bone marrow stromal cells and osteoblasts after fracture.\u00a0<\/p>\n
Further, the researchers investigated the origin of these bone-forming cells. Although similar cells are also found in the periosteum, their experiments showed that skeletal muscle is the main source. Even after the periosteum was surgically removed before injury, Clec3b-positive\u00a0cells still reached the fracture site and developed into bone-forming cells. Bone grafts that included surrounding muscle generated\u00a0substantially more\u00a0Clec3b-lineage bone-forming cells than grafts without muscle,\u00a0indicating\u00a0that skeletal muscle is the primary source of these regenerative cells.\u00a0<\/p>\n
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,\u00a0Clec3b-lineage cells differentiated into cartilage- and bone-forming cells, becoming a major source of this abnormal bone.\u00a0“When\u00a0we\u00a0blocked a key pathway\u00a0required\u00a0for bone formation or depleted these cells, both fracture healing and abnormal bone growth were significantly reduced. This finding\u00a0highlights\u00a0their\u00a0important role\u00a0in both\u00a0processes,”shares\u00a0Dr. Ayturk.\u00a0<\/p>\n
The researchers believe these cells could become promising therapeutic targets. Activating them may enhance fracture healing, while limiting their bone-forming activity could help prevent unwanted bone growth following serious injuries.\u00a0<\/p>\n
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