Abstract
Increases in mechanical loading can enhance the addition of new bone, altering geometry and density such that bones better withstand higher forces. Bone-forming osteoblasts have long been thought to originate from progenitors, but the exact source is yet to be identified. Previous studies indicate osteogenic precursors arise from Prx1-expressing progenitors during embryonic development and adult fracture repair. However, it is unknown whether this cell population is also a source for mechanically induced active osteoblasts. We first identified that Prx1 is expressed in skeletally mature mouse periosteum, a thin tissue covering the surface of the bone that is rich in osteoprogenitors. We then traced Prx1 progenitor lineage using a transgenic mouse model carrying both a Prx1-driven tamoxifen-inducible Cre and a ROSA-driven lacZ reporter gene. Cells that expressed Prx1 when compressive axial loading was applied were detected within the cortical bone days after stimulation, indicating osteocytes are of Prx1-expressing cell origin. In addition, we evaluated how these cells sense and respond to physical stimulation in vivo by disrupting their primary cilia, which are antenna-like sensory organelles known to enhance mechanical and chemical signaling kinetics. Although Prx1-driven primary cilium disruption did not affect osteoblast recruitment to the bone surface, the relative mineral apposition and bone formation rates were decreased by 53% and 34%, respectively. Thus, this cell population contributes to load-induced bone formation, and primary cilia are needed for a complete response. Interestingly, Prx1-expressing progenitors are easily extracted from periosteum and are perhaps an attractive alternative to marrow stem cells for bone tissue regeneration strategies.
Highlights
One way the skeleton structurally adapts to its mechanical environment is by stimulating the addition of new bone and subsequently altering its geometry and density to better withstand higher forces
paired-related homeobox 1 (Prx1)-expressing cells treated with the active compound of tamoxifen had visually shorter cilia compared to vehicle controls (Figure 1(b))
We explored whether Prx1-expressing cells require primary cilia to contribute to adult bone formation
Summary
One way the skeleton structurally adapts to its mechanical environment is by stimulating the addition of new bone and subsequently altering its geometry and density to better withstand higher forces. Bone formation in response to mechanical loading involves multiple cell types and requires a sequence of events to occur. Mechanosensitive osteocytes sense physical loading and secrete paracrine factors that recruit cells to the bone surface [1]. These cells eventually transform into matrix-producing osteoblasts and, potentially, embedded osteocytes. Bone-forming cells have long been thought to originate from progenitors, so approaches were developed to extract osteoblast precursors from bone marrow. These procedures are very invasive, and the acquired progenitors require further treatment in order to encourage proper differentiation. An appealing alternative is to harvest periosteum, which surrounds bones and is rich in progenitor cells known to preferentially differentiate towards the osteogenic lineage [2,3,4]
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