Cellular Plasticity in Musculoskeletal Development, Regeneration, and Disease

Kaji, Deepak; Tan, Zhijia; Johnson, Gemma; Huang, Wesley; Vasquez, Kaetlin; Lehoczky, Jessica A.; Lévi, Benjamin; Cheah, Kathryn S.E.; Huang, Alice H.

doi:10.1002/jor.24523

Cited by 5 publications

(9 citation statements)

References 110 publications

(268 reference statements)

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“…This has been enabled in part by modern genetic labeling of cells for fate mapping. Our work and others has now clearly demonstrated that chondrocytes give rise to the new bone during repair of fractures in appendicular and facial bones (Bahney et al 2019;Kaji et al 2020;Wong et al 2021). Chondrocytes also contribute to the osteoblast lineage during long bone development.…”

Section: Models Of Endochondral Ossificationsupporting

confidence: 64%

“…The concept gained popularity in the 1800s, was based on histological and anatomical observations, and is often discussed in terms of pathological changes in tissue in response to environmental insult such as with Barrett’s esophagus (Zhang et al 2021) or in the context of cancer as reviewed (Giroux and Rustgi 2017). However, recent evidence suggests that metaplasia and cellular plasticity contribute to development and regeneration within the musculoskeletal system and beyond (Kaji et al 2020; Brown et al 2022; Goldenring and Mills 2022). Metaplasia appears to be common in normal and pathologic processes in multicellular organisms.…”

Section: Paligenosis: a Process Of Metaplasia In Multicellular Organismsmentioning

confidence: 99%

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A Shifting Paradigm: Transformation of Cartilage to Bone during Bone Repair

2022

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While formation and regeneration of the skeleton have been studied for a long period of time, significant scientific advances in this field continue to emerge based on an unmet clinical need to improve options to promote bone repair. In this review, we discuss the relationship between mechanisms of bone formation and bone regeneration. Data clearly show that regeneration is not simply a reinduction of the molecular and cellular programs that were used for development. Instead, the mechanical environment exerts a strong influence on the mode of repair, while during development, cell-intrinsic processes drive the mode of skeletal formation. A major advance in the field has shown that cell fate is flexible, rather than terminal, and that chondrocytes are able to differentiate into osteoblasts and other cell types during development and regeneration. This is discussed in a larger context of regeneration in vertebrates as well as the clinical implication that this shift in understanding presents.

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Section: Models Of Endochondral Ossificationsupporting

confidence: 64%

Section: Paligenosis: a Process Of Metaplasia In Multicellular Organismsmentioning

confidence: 99%

A Shifting Paradigm: Transformation of Cartilage to Bone during Bone Repair

2022

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“…Their switch to another lineage can occur through transdifferentiation (transition from one to another differentiated cell type) or through dedifferentiation (reversal to a progenitor state) followed by redifferentiation (into a different cell type) (1). While enforceable experimentally in many cells (e.g., induction of pluripotent stem cells), it has been documented to this date in only a discrete number of events in vivo (e.g., epithelial-to-mesenchymal transition, cancer, and heterotopic ossification) (2)(3)(4). Thorough evaluation of cellular plasticity prevalence and underpinnings are prerequisites to understanding normal and disease processes and eventually tailor efficient disease treatments.…”

mentioning

confidence: 99%

SOX9 keeps growth plates and articular cartilage healthy by inhibiting chondrocyte dedifferentiation/osteoblastic redifferentiation

Haseeb

Angelozzi

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

137

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Cartilage is essential throughout vertebrate life. It starts developing in embryos when osteochondroprogenitor cells commit to chondrogenesis, activate a pancartilaginous program to form cartilaginous skeletal primordia, and also embrace a growth-plate program to drive skeletal growth or an articular program to build permanent joint cartilage. Various forms of cartilage malformation and degeneration diseases afflict humans, but underlying mechanisms are still incompletely understood and treatment options suboptimal. The transcription factor SOX9 is required for embryonic chondrogenesis, but its postnatal roles remain unclear, despite evidence that it is down-regulated in osteoarthritis and heterozygously inactivated in campomelic dysplasia, a severe skeletal dysplasia characterized postnatally by small stature and kyphoscoliosis. Using conditional knockout mice and high-throughput sequencing assays, we show here that SOX9 is required postnatally to prevent growth-plate closure and preosteoarthritic deterioration of articular cartilage. Its deficiency prompts growth-plate chondrocytes at all stages to swiftly reach a terminal/dedifferentiated stage marked by expression of chondrocyte-specific (Mgp) and progenitor-specific (Nt5e and Sox4) genes. Up-regulation of osteogenic genes (Runx2, Sp7, and Postn) and overt osteoblastogenesis quickly ensue. SOX9 deficiency does not perturb the articular program, except in load-bearing regions, where it also provokes chondrocyte-to-osteoblast conversion via a progenitor stage. Pathway analyses support roles for SOX9 in controlling TGFβ and BMP signaling activities during this cell lineage transition. Altogether, these findings deepen our current understanding of the cellular and molecular mechanisms that specifically ensure lifelong growth-plate and articular cartilage vigor by identifying osteogenic plasticity of growth-plate and articular chondrocytes and a SOX9-countered chondrocyte dedifferentiation/osteoblast redifferentiation process.

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“…Importantly, in vitro results cannot be directly translated to in vivo situation. Notably, in vivo studies using mouse models proposed that HO precursors could originate from skeletal muscle endothelial, “mesenchymal” or pericyte populations or tendon and connective tissue cells or even circulating stem/precursor cells [ 1 , 5 , 21 , 137 ]. Some initial studies suggested that endothelial cells, characterized by the presence of TIE2, which is the tyrosine kinase receptor for angiopoetin, are engaged in HO formation [ 138 , 139 ].…”

Section: Heterotopic Ossification Precursor Cellsmentioning

confidence: 99%

“…In human, however, such cells are not precisely described yet. Moreover, it is also suggested that different types of cells could be responsible for HO development dependently of HO type [ 1 , 5 , 21 , 137 ].…”

Section: Heterotopic Ossification Precursor Cellsmentioning

confidence: 99%

The Survey of Cells Responsible for Heterotopic Ossification Development in Skeletal Muscles—Human and Mouse Models

Pulik

Mierzejewski

Ciemerych

et al. 2020

Cells

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Heterotopic ossification (HO) manifests as bone development in the skeletal muscles and surrounding soft tissues. It can be caused by injury, surgery, or may have a genetic background. In each case, its development might differ, and depending on the age, sex, and patient’s conditions, it could lead to a more or a less severe outcome. In the case of the injury or surgery provoked ossification development, it could be, to some extent, prevented by treatments. As far as genetic disorders are concerned, such prevention approaches are highly limited. Many lines of evidence point to the inflammatory process and abnormalities in the bone morphogenetic factor signaling pathway as the molecular and cellular backgrounds for HO development. However, the clear targets allowing the design of treatments preventing or lowering HO have not been identified yet. In this review, we summarize current knowledge on HO types, its symptoms, and possible ways of prevention and treatment. We also describe the molecules and cells in which abnormal function could lead to HO development. We emphasize the studies involving animal models of HO as being of great importance for understanding and future designing of the tools to counteract this pathology.

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Cellular Plasticity in Musculoskeletal Development, Regeneration, and Disease

Cited by 5 publications

References 110 publications

A Shifting Paradigm: Transformation of Cartilage to Bone during Bone Repair

A Shifting Paradigm: Transformation of Cartilage to Bone during Bone Repair

SOX9 keeps growth plates and articular cartilage healthy by inhibiting chondrocyte dedifferentiation/osteoblastic redifferentiation

The Survey of Cells Responsible for Heterotopic Ossification Development in Skeletal Muscles—Human and Mouse Models

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