Transcription Factors in Bone: Developmental and Pathological Aspects - Engineered Bone: Tissue Engineering Intelligence Unit - page 8

reduced peripheral B cells and defects in humoral responses in mice. 55 However, when both
P50 and P52 were deleted simultaneously, the mutant mice developed osteopetrosis as a result
of an arrest in osteoclast differentiation. Similar to Pu.1-deficient mice, the osteopetrotic phe-
notype can be rescued by bone marrow transplantation. 56 Lack of NF κ B impairs the expres-
sion of cytokines including IL-1, TNF α , and IL-6 that are also required for osteoclast matura-
tion.
Two mutant alleles at the microphthalmia (mi) locus have been isolated from mice showing
sclerosing bone dysplasias in skeleton. 57 Mi locus encodes a basic helix-loop-helix-leucine zip-
per (bHLH-Zip) transcription factor called microphthalmia transcription factor (MITF).
Heterodimerization of MITF with its closely related family members, TFEB, TFE3, and TFEc
enable them to bind and activate target genes. Both Mitf and Tfe3 are expressed at high levels
in osteoclasts. 58,59 Mutations in Mi cause mild osteopetrosis in mice due to defects in
osteoclastogenesis, providing a direct evidence that MITF is required for osteoclast differentia-
tion. MITF and TFE3 are also found to regulate osteoclast activity through controlling cathe-
psin K expression. 60 However, mutations in human homologue of the mouse Mi gene do not
lead to skeletal abnormality (see below).
Human Muations in Transcription Factors Affecting Skeletal
Development
Mutations affecting the DNA binding or the transactivation ability of transcription factors
in humans can affect many aspects of skeletogenesis. As a matter of fact, molecular elucidation
of many human skeletal dysplasias have been a major determinant in our improved under-
standing of skeletal development. There mutations can affect transcription factors regulating
skeletal patterning or transcription factors regulating cell differentiation. Mutation of genes
affecting patterning skeleton is best illustrated by the study of synpolydactyly, an autosomal
dominant disease caused by mutation in HoxD13. Synpolydactyly patients have a characteris-
tic manifestation in both hands and feet, typically have 3/4 finger and 4/5 toe syndactyly with
a duplicated digit in the syndactylous web. This condition is caused by expansions of a polyalanine
stretch in the amino-terminal region of HoxD13, 61,62 which impair the function of HoxD13
protein. Hox proteins are a family of transcription factors highly conserved from fruit fly to
man. They all contain a DNA-binding motif called homeodomain which is 60 amino acid
long. Hox genes are distributed in four different clusters and each of them contains 9 to 13
individual genes whose loci arranged in an order corresponding to their expression pattern. 63,64
HoxD13 is the 13 th gene of the 4 th cluster.
Msx1 and Msx2 genes belong to a unique homoebox gene subfamily since their loci are
outside of the 4 Hox clusters. Msx1 and Msx2 expression is restricted in the developing cranio-
facial complex. Consistently, haploinsufficiency of Msx1 in humans shows orofacial clefting 65
and tooth agenesis 66,67 and deletion of Msx1 in mice caused cleft palate and abnormalities of
craniofacial and tooth development. 68 Inactivation of Msx2 in humans gives rise to cranio-
synostosis, 69 an autosomal dominant disease characterized by craniofacial malformations or
enlarged parietal foramina (PFM) caused by deficient ossification around the parietal bones. 70,71
Mutations in human Msx2 can either affect its DNA-binding affinity leading to loss-of-function
mutation as in the case of PFM 70 or stabilize DNA binding of Msx2 to its target DNA leading
to gain-of-function mutation as in Boston type craniosynostosis. 72 Interestingly, the defects
caused by Msx2 mutation in mice are milder than those in humans. Cranial ossification defect
is limited to the central frontal bone in Msx2-null mutant mice but heterozygous mutant mice
are normal. 73
Another autosomal dominant disorders of craniosynostosis in humans is Saethre-Chotzen
syndrome (SCS), which is characterized by craniofacial and limb anomalies. Haplo-insuffi-
ciency of Twist, a transcription factor containing a basic helix-loop-helix motif, has been iden-
tified as the cause for SCS. 74,75 In veterbrates, Twist is expressed starting at 8 dpc. 76 Null-mutation
of this gene in mouse is embryonic lethal, the mutant embryos die around 11.5 dpc. 77