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The role of Meteorin-like in skeletal development and bone fracture healing.

ABSTRACT: Meteorin-like protein (Metrnl), homologous to the initially identified neurotrophic factor Meteorin, is a secreted, multifunctional protein. Here we used mouse models to investigate Metrnl's role in skeletal development and bone fracture healing. During development Metrnl was expressed in the perichondrium and primary ossification center. In neonates, single cell RNA-seq of diaphyseal bone demonstrated strongest expression of Metrnl transcript by osteoblasts. In vitro, Metrnl was osteoinductive, increasing osteoblast differentiation and mineralization in tissue culture models. In vivo, loss of Metrnl expression resulted in no change in skeletal metrics in utero, at birth, or during postnatal growth. Six-week-old Metrnl-null mice displayed similar body length, body weight, tibial length, femoral length, BV/TV, trabecular number, trabecular thickness, and cortical thickness as littermate controls. In 4-month-old mice, lack of Metrnl expression did not change structural stiffness, ultimate force, or energy to fracture of femora under 3-point-bending. Last, we investigated the role of Metrnl in bone fracture healing. Metrnl expression increased in response to tibial injury, however, loss of Metrnl expression did not affect the amount of bone deposited within the healing tissue nor did it change the structural parameters of healing tissue. This work identifies Metrnl as a dispensable molecule for skeletal development. However, the osteoinductive capabilities of Metrnl may be utilized to modulate osteoblast differentiation in cell-based orthopedic therapies.

SUBMITTER: Huang R

PROVIDER: S-EPMC9309188 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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The role of Meteorin-like in skeletal development and bone fracture healing.

Huang Rong R Balu Abhinav R AR Molitoris Kristin H KH White James P JP Robling Alexander G AG Ayturk Ugur M UM Baht Gurpreet S GS

Journal of orthopaedic research : official publication of the Orthopaedic Research Society 20220208 11

Meteorin-like protein (Metrnl), homologous to the initially identified neurotrophic factor Meteorin, is a secreted, multifunctional protein. Here we used mouse models to investigate Metrnl's role in skeletal development and bone fracture healing. During development Metrnl was expressed in the perichondrium and primary ossification center. In neonates, single cell RNA-seq of diaphyseal bone demonstrated strongest expression of Metrnl transcript by osteoblasts. In vitro, Metrnl was osteoinductive, ...[more]

PMID: 35076116

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Project description:The fracture hematoma that forms between the broken fragments of bone serves as a natural fibrin scaffold. However, there is no data regarding the differences between the micro-architectural and biological properties of hematomas formed in normally healing, delayed healing, and non-healing bone defects. Mimicking these three conditions in the rat femur, we demonstrate clear differences in fibrin clot morphology, which directly affect the gene expression pattern. Specifically, RNA-sequencing reveals that the expression of essential osteogenic genes in normally healing defects are significantly up-regulated, whereas in delayed and non-healing defects they are down-regulated. Surprisingly, there were no substantial differences between delayed and non-healing defects. Most importantly, this study demonstrates that the healing outcome has already been determined at the earliest stage of bone healing. These findings could be used to develop biomaterial scaffolds mimicking the micro-architectural properties of normally healing fracture hematoma as a treatment strategy for bone defects. The hypothesis of this study was that the micro-architectural properties of the initially formed hematoma has a significant effect on the regulation of the biological process at the fracture site, which ultimately determines the outcome of bone healing. Three different healing models were investigated - normally healing, delayed healing, and non-healing defects. The results demonstrated that the intrinsic micro-architectural properties of hematomas between those groups varied distinctly in terms of fiber diameter, porosity, and density of the formed fibrin network. Those differences influenced biological responses, as evidenced by a higher expression of osteogenic genes in normally healing compared to delayed and non-healing defects, and the failed activation of BMP-2 in non-healing defects. More importantly, our results demonstrate healing outcomes are already determined at the initial (hematoma) stage of bone healing.

Dataset Information

The role of Meteorin-like in skeletal development and bone fracture healing.

Publications

The role of Meteorin-like in skeletal development and bone fracture healing.

Similar Datasets

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