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Review
. 2020 Nov;21(11):696-711.
doi: 10.1038/s41580-020-00279-w. Epub 2020 Sep 8.

Mechanisms of bone development and repair

Ankit Salhotra #  1   2 , Harsh N Shah #  1   2 , Benjamin Levi  3 , Michael T Longaker  4   5
Affiliations
Review

Mechanisms of bone development and repair

Ankit Salhotra et al. Nat Rev Mol Cell Biol. 2020 Nov.

Abstract

Bone development occurs through a series of synchronous events that result in the formation of the body scaffold. The repair potential of bone and its surrounding microenvironment - including inflammatory, endothelial and Schwann cells - persists throughout adulthood, enabling restoration of tissue to its homeostatic functional state. The isolation of a single skeletal stem cell population through cell surface markers and the development of single-cell technologies are enabling precise elucidation of cellular activity and fate during bone repair by providing key insights into the mechanisms that maintain and regenerate bone during homeostasis and repair. Increased understanding of bone development, as well as normal and aberrant bone repair, has important therapeutic implications for the treatment of bone disease and ageing-related degeneration.

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Conflict of interest statement

Competing interests

The authors declare no competing interests.

Figures

Fig. 1 |
Fig. 1 |. Bone homeostasis.
Bone homeostasis is achieved through the activity of osteoblast lineage cells and osteoclast lineage cells. Osteoblast lineage cells such as the osteoid (which is the unmineralized portion of bone matrix) secrete hydroxyapatite and calcium to promote bone mineralization and the formation of osteocytes. Osteoclast lineage cells resorb bone. The balance between the activity of the two cell lineages results in bone homeostasis. HSC, haematopoietic stem cell.
Fig. 2 |
Fig. 2 |. Skeletal stem cell hierarchy.
Skeletal stem cells (SSCs) (and their progenitors) in mice and humans can be isolated on the basis of distinctive immunophenotypic cell surface markers. a | Human SSC hierarchy immunophenotypic profile, beginning with a human SSC at the apex, differentiating into a human bone, cartilage and stromal progenitor and into its committed progenitors: human cartilage progenitors, human osteoprogenitors and human stromal cells. b | Mouse SSC immunophenotypic profile, beginning with a mouse SSC at the apex, differentiating into a mouse bone, cartilage and stromal progenitor and into its committed progenitors: mouse cartilage progenitors, mouse osteoprogenitors, mouse B lymphocyte stromal progenitors, mouse 6C3 cells and mouse hepatic leukaemia factor-expressing cells.
Fig. 3 |
Fig. 3 |. Long bone anatomy.
The metaphysis contains the epiphyseal growth plate, the site of new longitudinal bone growth. This area can be categorized into five zones: the reserve, proliferative, hypertrophy, calcification and ossification zones. The reserve zone contains quiescent chondrocytes found towards the epiphyseal end of the bone. The proliferative zone contains chondrocytes that undergo rapid proliferation. The hypertrophy zone contains chondrocytes that stop proliferating and begin to undergo rapid growth. The calcified zone contains cells that begin to undergo apoptosis and their matrix begins to calcify. The ossification zone contains mature and terminally committed osteoblasts that help lay down mineralized bone.
Fig. 4 |
Fig. 4 |. Developmental signalling pathways regulating osteoblast differentiation.
Various signalling pathways function in a coordinated manner to ensure appropriate bone development and repair. a | Mesenchymal progenitors (MP) are initially marked by SOX9+ expression committing them to the osteochondroprogenitor lineage. Indian hedgehog (IHH) binds to Smoothened homologue (SMO) to prevent the cleavage of GLI3 to GLI3 repressor (GLI3R) and to activate GLI2 activator (GLI2A), thus leading to expression of SOX9 and Runt-related transcription factor 2 (RUNX2) in osteochondroprogenitor cells. b | Notch signalling is a negative regulator of osteoblast differentiation. Notch binding to Jagged (JAG) or Delta-like protein (DLL) causes proteolytic cleavage of Notch, allowing Notch intracellular domain (NCID) to interact with RBPJ and Mastermind-like protein 1 (MAML1) to affect the downstream targets Hairy and Enhancer of Split (HES) and HES-related with YRPW motif (HEY), leading to the inhibition of osteoblast differentiation. c | Canonical WNT signalling acts as a positive regulator of osteoblast differentiation. WNT ligand binding to low-density lipoprotein receptor-related protein (LRP5) or LRP6 and Frizzled (FZD) leads to the accumulation of β-catenin, thus allowing its translocation to the nucleus to affect gene expression, including increasing the expression of RUNX2 and osterix (OSX), which marks the commitment to mature osteoblasts. d | Bone morphogenetic protein (BMP) signalling induces osteoblast differentiation. Binding of BMP2 or BMP4 leads to the phosphorylation of SMAD1, SMAD5 or SMAD8. They form a complex with SMAD4 and then enter the nucleus to control gene expression, allowing the transition of RUNX2+OSX+ cells to mature osteoblasts. e | Fibroblast growth factor (FGF) binds to cell surface tyrosine kinase FGF receptors (FGFR1-FGFR4), leading to a cascade of intracellular signalling events. FGF signalling controls preosteoblast proliferation, osteoblast differentiation and the function of mature osteoblasts. BMPR-I, bone morphogenetic protein receptor type 1; BMPR-II, bone morphogenetic protein receptor type 2; PKC, protein kinase C; PS, presenilin; PTCH1, Patched homologue 1.
Fig. 5 |
Fig. 5 |. Continuum of bone disorders.
Bone disorders are characterized by a gradient from ‘less bone’ to ‘too much bone’. Beginning on the left side of the spectrum, the non-union fracture with fibrosis within the gap indicates no bone is present. On appropriate healing, the osteotomy site is filled with a new bone regenerate. Next, hip fracture results in a bicortical defect in the femoral head. A greenstick fracture results in a unicortical defect on one side of the bone. In the middle is bone homeostasis, which is represented by a physiologically normal bone. On the right end of the spectrum is too much bone, which is represented by the pathology of heterotopic ossification, wherein extraskeletal bone formation occurs.
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