Vital Roles of Tendon in Mandibular Bone and Hypophosphatemia-caused Osteosclerosis

Objectives: The current belief is that tendon (connecting muscles to bone) simply controls body movement and stabilizes joints via an interface named enthesis (a dense fibrocartilage). The goal of this study is to test novel roles of tendon in mandibular bone ridge growth and pathological roles of tendon in hypophosphatemic rickets-caused osteosclerosis.
Methods: We generated compound tracing reporter mice containing Rosa 26 tdTomato, Scx-Cre^ERT2 (tendon-specific) with tamoxifen injections at postnatal day-3. We harvested at weeks-2, -7 and -10 to define how the Scx+-tendon cells contribute to mandibular bone ridge formation in the background with and without removing Dmp1 (a hypophosphatemic rickets model).
Results: The cell lineage tracing data showed: 1) The initial labeled tendon cells connected to masseter were first changed into dendritic fibroblasts and then chondrocyte-like cells followed by bone cells; 2) The tendon-attached rough bone ridges, more porous than the periosteum-derived bone (smooth and dense bone), were formed by tendon-derived bone cells, which were irregular in shape, disorganized in cell distribution pattern, and were rich with ER-Golgi complex as compared to a regular periosteum-derived bone cell (spindle in shape, well organized in cell distribution with few ER-Golgi complexes) at a EM level; 3) These tendon-originated bone cells expressed a mixture of extracellular matrix markers of tendon, cartilage and bone, including SOX9, RUNX2, periostin, aggrecan, Col X and Col I, as well as alkaline phosphatase; and 4) There were more expanded bone ridges in Dmp1 KO mandibles, which were formed by tendon-derived cells due to hypophosphatemia.
Conclusions: This study identified a 3^rd-type of bone that is directly formed by tendon with a mixture of tendon-bone-cartilage matrices. More importantly, in the hypophosphatemic rickets model (Dmp1 KO), there are more osteosclerotic lesions directly originated from tendon cells, which help to explain why patients with rickets display osteosclerosis.