A new paradigm has emerged for osteogenesis imperfecta as a collagen-related disorder. The more prevalent autosomal dominant forms of osteogenesis imperfecta are caused by primary defects in type I collagen, whereas autosomal recessive forms are caused by deficiency of proteins which interact with type I procollagen for post-translational modification and/or folding. Factors that contribute to the mechanism of dominant osteogenesis imperfecta include intracellular stress, disruption of interactions between collagen and noncollagenous proteins, compromised matrix structure, abnormal cell-cell and cell-matrix interactions and tissue mineralization. Recessive osteogenesis imperfecta is caused by deficiency of any of the three components of the collagen prolyl 3-hydroxylation complex. Absence of 3-hydroxylation is associated with increased modification of the collagen helix, consistent with delayed collagen folding. Other causes of recessive osteogenesis imperfecta include deficiency of the collagen chaperones FKBP10 or Serpin H1. Murine models are crucial to uncovering the common pathways in dominant and recessive osteogenesis imperfecta bone dysplasia. Clinical management of osteogenesis imperfecta is multidisciplinary, encompassing substantial progress in physical rehabilitation and surgical procedures, management of hearing, dental and pulmonary abnormalities, as well as drugs, such as bisphosphonates and recombinant human growth hormone. Novel treatments using cell therapy or new drug regimens hold promise for the future.

New perspectives on osteogenesis imperfecta.

Runx2 is essential for osteoblast differentiation and chondrocyte maturation. During osteoblast differentiation, Runx2 is weakly expressed in uncommitted mesenchymal cells, and its expression is upregulated in preosteoblasts, reaches the maximal level in immature osteoblasts, and is down-regulated in mature osteoblasts. Runx2 enhances the proliferation of osteoblast progenitors by directly regulating Fgfr2 and Fgfr3. Runx2 enhances the proliferation of suture mesenchymal cells and induces their commitment into osteoblast lineage cells through the direct regulation of hedgehog (Ihh, Gli1, and Ptch1), Fgf (Fgfr2 and Fgfr3), Wnt (Tcf7, Wnt10b, and Wnt1), and Pthlh (Pthr1) signaling pathway genes, and Dlx5. Runx2 heterozygous mutation causes open fontanelle and sutures because more than half of the Runx2 gene dosage is required for the induction of these genes in suture mesenchymal cells. Runx2 regulates the proliferation of osteoblast progenitors and their differentiation into osteoblasts via reciprocal regulation with hedgehog, Fgf, Wnt, and Pthlh signaling molecules, and transcription factors, including Dlx5 and Sp7. Runx2 induces the expression of major bone matrix protein genes, including Col1a1, Spp1, Ibsp, Bglap2, and Fn1, in vitro. However, the functions of Runx2 in differentiated osteoblasts in the expression of these genes in vivo require further investigation.

Regulation of Proliferation, Differentiation and Functions of Osteoblasts by Runx2.

RUNX2 is an essential transcription factor for osteoblast differentiation and chondrocyte maturation. SP7, another transcription factor, is required for osteoblast differentiation. Major signaling pathways, including FGF, Wnt, and IHH, also play important roles in skeletal development. RUNX2 regulates Sp7 expression at an early stage of osteoblast differentiation. FGF2 upregulates Runx2 expression and activates RUNX2, and gain-of-function mutations of FGFRs cause craniosynostosis and limb defect with upregulation of Runx2 expression. Wnt signaling upregulates Runx2 expression and activates RUNX2, and RUNX2 induces Tcf7 expression. IHH is required for Runx2 expression in osteoprogenitor cells during endochondral bone development, and RUNX2 directly regulates Ihh expression in chondrocytes. Thus, RUNX2 regulates osteoblast differentiation and chondrocyte maturation through the network with SP7 and with FGF, Wnt, and IHH signaling pathways during skeletal development.

Signaling networks in RUNX2-dependent bone development.

Mechanisms of bone repair and regeneration.

Runx2 is a transcription factor that is essential for osteoblast differentiation and chondrocyte maturation. Ihh, expressed in prehypertrophic and hypertrophic chondrocytes, is required for the specification of Runx2+ osteoprogenitors in endochondral bone development. Runx2 induces Sp7, an essential transcription factor for osteoblast differentiation. Canonical Wnt signaling is also required for osteoblast differentiation. Runx2+ osteoprogenitors retain the capacity to differentiate into chondrocytes, and Sp7 and canonical Wnt signaling direct cells to osteoblasts, thereby inhibiting chondrocyte differentiation. The function of Runx2 after the commitment to osteoblasts remains controversial. Runx3 has a redundant function with Runx2 in chondrocyte maturation. Runx2 regulates the expression of Ihh, Col10a1, Spp1, Ibsp, Mmp13, and Vegfa in the respective layers in growth plates. Runx2 enhances chondrocyte proliferation through the induction of Ihh. Ihh induces Pthlh, which inhibits Runx2 and chondrocyte maturation, forming a negative feedback loop for chondrocyte maturation. Runx2 is one of the genes responsible for the pathogenesis of osteoarthritis (OA) because RUNX2 is up-regulated in chondrocytes in OA cartilage and a germline haplodeficiency or deletion of Runx2 in articular chondrocytes decelerates OA progression. Runx2 plays an important role in the bone metastasis of breast and prostate cancers by up-regulating Spp1, Ibsp, Mmp9, Mmp13, Vegfa, Tnfsf11, and Ihh expression and down-regulating Tnfrsf11b expression. Cbfb forms a heterodimer with Runx2 and is required for the efficient DNA binding of Runx2. Cbfb stabilizes Runx proteins at different levels among Runx family proteins by inhibiting their ubiquitination-mediated degradation. Cbfb plays more important roles in endochondral ossification than in intramembranous ossification.

Runx2, an inducer of osteoblast and chondrocyte differentiation

Osterix (Osx) is essential for osteoblast differentiation and bone formation, because mice lacking Osx die within 1 h of birth with a complete absence of intramembranous and endochondral bone formation. Perinatal lethality caused by the disruption of the Osx gene prevents studies of the role of Osx in bones that are growing or already formed. Here, the function of Osx was examined in adult bones using the time- and site-specific Cre/loxP system. Osx was inactivated in all osteoblasts by Col1a1-Cre with the activity of Cre recombinase under the control of the 2.3-kb collagen promoter. Even though no bone defects were observed in newborn mice, Osx inactivation with 2.3-kb Col1a1-Cre exhibited osteopenia phenotypes in growing mice. BMD and bone-forming rate were decreased in lumbar vertebra, and the cortical bone of the long bones was thinner and more porous with reduced bone length. The trabecular bones were increased, but they were immature or premature. The expression of early marker genes for osteoblast differentiation such as Runx2, osteopontin, and alkaline phosphatase was markedly increased, but the late marker gene, osteocalcin, was decreased. However, no functional defects were found in osteoclasts. In summary, Osx inactivation in growing bones delayed osteoblast maturation, causing an accumulation of immature osteoblasts and reducing osteoblast function for bone formation, without apparent defects in bone resorption. These findings suggest a significant role of Osx in positively regulating osteoblast differentiation and bone formation in adult bone.

Positive Regulation of Adult Bone Formation by Osteoblast-Specific Transcription Factor Osterix†‡

Osterix (Osx) is an essential transcription factor for osteoblast differentiation and bone formation. Osx knockout show a complete absence of bone formation, whereas Osx conditional knockout in osteoblasts produce an osteopenic phenotype after birth. Here, we questioned whether Osx has a potential role in regulating physiological homeostasis. In Osx heterozygotes expressing low levels of Osx in bones, the expression levels of pro-inflammatory cytokines were significantly elevated, indicating that reduced Osx expression may reflect an inflammatory-prone state. In particular, the expression of interleukin-6, a key mediator of chronic inflammation, was increased in Osx heterozygotes and decreased in Osx overexpressing osteoblasts, and transcriptionally down-regulated by Osx. Although no significant differences were revealed in renal morphology and function between Osx heterozygotes and wild-type under normoxic conditions, recovery of kidneys after ischemic damage was remarkably delayed in Osx heterozygotes, as indicated by elevated blood urea nitrogen and creatinine levels, and by morphological alterations consistent with acute tubular necrosis. Eventually, protracted low Osx expression level caused an inflammatory-prone state in the body, resulting in the enhanced susceptibility to renal injury and the delayed renal repair after ischemia/reperfusion. This study suggests that the maintenance of Osx expression in bone is important in terms of preventing the onset of an inflammatory-prone state.

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Min-A Lee

Papers

Positive Regulation of Adult Bone Formation by Osteoblast-Specific Transcription Factor Osterix†‡

Persistent Low Level of Osterix Accelerates Interleukin-6 Production and Impairs Regeneration after Tissue Injury