DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

Fibroblast Growth Factor 23 and Klotho
Fibroblast growth factor 23 (FGF23) is a hypophosphatemic
hormone whose actions generally parallel
those of PTH but with effects restricted to regulation of
renal P i
absorption and vitamin D biosynthesis. Klotho
is a membrane protein that serves as an essential cofactor
in the transduction of FGF23 signaling.
FGF23 was discovered by positional cloning as the gene
responsible for autosomal dominant hypophosphatemic rickets
(ADHR). It was simultaneously cloned as one factor causing tumorinduced
osteomalacia (TIO). FGF23, a protein of 251 amino acids,
is produced primarily by several bone cells including osteoblasts,
osteocytes, and lining cells.
FGF23 is secreted in response to dietary phosphorus load,
and its main function is the promotion of urinary phosphate excretion
and the suppression of active vitamin D production by the kidney.
Emerging evidence suggests that FGF23 is the principal
regulator of proximal renal tubule phosphate reabsorption and of
1,25-dihydroxyvitamin D synthesis. Serum levels of FGF23 rise precipitously
in patients with chronic kidney disease and are inversely
correlated with the degree of hyperphosphatemia. Elevated FGF23
may contribute to impaired production of 1,25-dihydroxyvitamin D.
Klotho was originally identified as a gene mutated in mice that
developed accelerated aging. Further analysis revealed a pattern of
altered mineral ion metabolism and diminished bone density similar
to that found in FGF23 knockout mice or patients with ADHR. The
similar phenotypes of Klotho-deficient and FGF23-null mice suggested
that Klotho and FGF23 function in a common signaling pathway.
Klotho acts as a cofactor in FGF signaling, facilitates the
interactions of FGF23 with its receptor, and determines its tissue specificity
(Razzaque, 2009). Exogenous FGF23 administration reduces
serum P i
and calcitriol synthesis. Vitamin D analogs are commonly
used in the management of chronic kidney disease. Although no
clinical agents based on FGF23 have yet been developed, bioactive
fragments or FGF23 inhibitors might become useful in counterbalancing
the hyperphosphatemic actions of vitamin D therapy.
BONE PHYSIOLOGY
The skeleton is the primary structural support for the
body and also provides a protected environment for
hematopoiesis. It contains both a large mineralized
matrix and a highly active cellular compartment.
Skeletal Organization. It is useful to consider the appendicular, or
peripheral, skeleton as separate from the axial, or central, skeleton
because their turnover rates differ. Appendicular bones make up 80%
of bone mass and are composed predominantly of compact cortical
bone. Axial bones, such as the spine and pelvis, contain substantial
amounts of trabecular bone within a thin cortex. Trabecular bone
consists of highly connected bony plates that resemble a honeycomb.
The intertrabecular interstices contain bone marrow and fat.
Alterations in bone turnover are observed first and foremost in axial
bone both because bone surfaces, where bone remodeling occurs,
are more densely distributed in trabecular bone and because marrow
precursor cells that ultimately participate in bone turnover lie in close
proximity to trabecular surfaces.
Bone Mass. Bone mineral density (BMD) and fracture risk in later
years reflect the maximal bone mineral content at skeletal maturity
(peak bone mass) and the subsequent rate of bone loss. Major
increases in bone mass, accounting for ~60% of final adult levels,
occur during adolescence, mainly during years of highest growth
velocity. Bone acquisition is largely complete by age 17 in girls and
by age 20 in boys. Inheritance accounts for much of the variance in
bone acquisition; other factors include circulating estrogen and
androgens, physical activity, and dietary calcium.
Bone mass peaks during the third decade, remains stable
until age 50, and then declines progressively. Similar trajectories
occur for men and women of all ethnic groups. The fundamental
accuracy of this model has been amply confirmed for cortical bone,
although trabecular bone loss at some sites probably begins prior
to age 50. In women, loss of estrogen at menopause accelerates the
rate of bone loss. Primary regulators of adult bone mass include
physical activity, reproductive endocrine status, and calcium
intake. Optimal maintenance of BMD requires sufficiency in all
three areas, and deficiency of one is not compensated by excessive
attention to another.
Bone Remodeling. Growth and development of endochondral bone
are driven by a process called modeling. Once new bone is laid
down, it is subject to a continuous process of breakdown and renewal
called remodeling, by which bone mass is adjusted throughout adult
life (Ballock and O’Keefe, 2003). Remodeling is carried out by myriad
independent “bone remodeling units” throughout the skeleton
(Figure 44–8). Remodeling proceeds on bone surfaces, ~90% of
which are normally inactive, covered by a thin layer of lining cells.
In response to physical or biochemical signals, recruitment of marrow
precursor cells to the bone surface results in their fusion into
the characteristic multinucleated osteoclasts that resorb, or excavate,
a cavity into the bone.
Osteoclast production is regulated by osteoblast-derived
cytokines such as IL-1 and IL-6. Studies have begun to clarify the
mechanisms through which osteoclast production is regulated (Suda
et al., 1999). The receptor for activating NF-κB (RANK) is an osteoclast
protein whose expression is required for osteoclastic bone
resorption. Its natural ligand, RANK ligand (RANKL; previously
called osteoclast differentiation factor), is a membrane-spanning
osteoblast protein. On binding to RANK, RANKL induces osteoclast
formation (Khosla, 2001) (Figure 44–9). RANKL initiates the
activation of mature osteoclasts, as well as the differentiation of
osteoclast precursors. Osteoblasts produce osteoprotegerin (OPG),
which acts as a decoy ligand for RANKL. Under conditions favoring
increased bone resorption, such as estrogen deprivation, OPG is
suppressed, RANKL binds to RANK, and osteoclast production
increases. When estrogen sufficiency is reestablished, OPG increases
and competes effectively with RANKL for binding to RANK. In certain
model systems, OPG is superior to bisphosphonates in suppressing
bone resorption and hypercalcemia (Morony et al., 2005).
Completion of the resorption phase is followed by invasion of
preosteoblasts derived from marrow stroma into the base of the
resorption cavity. These cells develop the characteristic osteoblastic
phenotype and begin to replace the resorbed bone by elaborating new
bone matrix constituents, such as collagen and osteocalcin. Once the
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CHAPTER 44
AGENTS AFFECTING MINERAL ION HOMEOSTASIS AND BONE TURNOVER