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CHAPTER
4
Mineralized Tissue: Histology, Biology
and Biochemistry
Adele L. Boskey and Stephen B. Doty
Hospital for Special Surgery, Affiliated with Weil Medical College of Cornell University,
New York, NY, USA
INTRODUCTION
Biosynthesis and Post-Translational Modifications of
Collagens (Hans Peter Bachinger and Jay R. Shapiro) and
Collagen Structure, Folding and Function (Sergey Leikin,
Elena Makareeva and Jay R. Shapiro)).
Molecular modeling
10
of the material properties
caused by point defects in collagen demonstrated that a
single point mutation could lead the entire bone to “cata-
strophic” fracture due to helical disruption that weakens
the matrix. This model did not explain why in OI the
bone does not mineralize properly, but this improper
mineralization contributes to the “brittle phenotype.” We
suggest that it is the NCP-collagen and NCP-collagen-
mineral interaction(s) that affect the brittleness. The best
available evidence, that it is the NCPs and not the colla-
gen alone that cause the mineralization abnormality in
OI, come from a study
11
in which intrauterine transplan-
tation of human marrow into mice with a premature ter-
mination sequence in the alpha-2 chain of type I collagen
at 8 weeks produced normal heterogeneous type I colla-
gen and corrected some mechanical properties (fracture
incidence), but did not correct the mineralization defect.
In addition, the observation that dentinogenesis imper-
fecta (DI) with similar features occurs both in DI patients
with OI and collagen mutations, and in DI patients with
mutations only in the NCP dentin sialophosphoprotein,
dspp gene.
12
Similarly, the DI phenotype in dspp KO
mice, with no collagen abnormalities
13
points to roles for
both collagen and NCPs in the mineralization process.
The Kaplan group
14
showed small collagen-like
sequences made into self-assembled monolayers when
incubated repeatedly in calcium and then phosphate
solutions formed apatite crystals with different hab-
its which depended on the substitution in the collagen
Collagen is the most abundant protein in the human
body and type I collagen, the predominant type found in
bones, teeth, lungs and blood vessels, is the most abun-
dant of the 27 or more types identified to date. One of the
features of the fibrous collagen matrix is their ability to
bind a number of different proteins and cells at specific
sites on the collagen fibrils.1
1
It is thus not surprising that
genetic defects in type I collagen manifest themselves
predominantly in bone and that other noncollagenous
protein (NCP) abnormalities are often associated with
these collagen defects. To appreciate the significance
of the role of collagen in mineralization and the role of
NCPs in this process, this chapter will review the salient
features of mammalian bone mineralization, discuss how
normal mineralization occurs, and the alterations in min-
eralization that occur when collagen structure and pro-
cessing is altered. We will discuss methods for evaluation
of bone mineralization patterns and give examples from
humans and animal models of osteogenesis imperfecta
(OI) and their wild-type controls.
Studies of mineralized tissues from patients with dif-
ferent forms of OI and animal models of this “brittle
bone” disease
2-6
suggest that collagen, often claimed in
the literature to have “no effect” on mineralization,
7
has
a definite role - although it may be indirect, perhaps by
changing the conformation of the intrinsically disordered
(IDP) NCPs most of which normally bind to type I colla-
gen.
8
With minor exceptions (e.g.,
9
) the mutations in OI
are involved in the synthesis, post-translational modifica-
tion, trafficking, processing, or secretion of type I collagen
(see Chapters 6 and 7, The Collagen Folding Machinery:
