PTHrP and Skeletal Development
HENRY M. KRONENBERG
Endocrine Unit, Massachusetts General Hospital and Harvard Medical School,
Boston, Massachusetts 02114, USA
ABSTRACT: Parathyroid hormone-related protein (PTHrP) participates
in the regulation of endochondral bone development. After the carti-
lage mold is established in fetal life, perichondrial cells and chondro-
cytes at the ends of the mold synthesize PTHrP. This ligand then acts
on PTH/PTHrP receptors on chondrocytes. As chondrocytes go through
a program of proliferation and then further differentiation into post-
mitotic, hypertrophic chondrocytes, PTHrP action keeps chondrocytes
proliferating and delays their further differentiation. Indian hedgehog
(Ihh) is synthesized by chondrocytes that have just stopped proliferat-
ing and is required for synthesis of PTHrP. The feedback loop between
PTHrP and Ihh serves to regulate the pace of chondrocyte differenti-
ation and the sites at which perichondrial cells first differentiate into
osteoblasts. Activation of the PTH/PTHrP receptor leads to stimula-
tion of both Gsand Gqfamily heterotrimeric G proteins. Genetic anal-
yses demonstrate that Gsactivation mediates the action of PTHrP to
Downstream from Gsactivation, synthesis of the cyclin-cdk inhibitor,
p57, is suppressed, thereby increasing the pool of proliferating chondro-
by the phosphorylation of the transcription factor, SOX9, and by sup-
These pathways and undoubtedly others cooperate to regulate the pace
of differentiation of growth plate chondrocytes in response to PTHrP.
KEYWORDS: parathyroid hormone-related protein; growth plate; chon-
drocytes; Indian hedgehog
exploring the physiologic roles of PTHrP. PTHrP was shown to be synthesized
in many types of cells, to activate the same receptor activated by PTH, and, to
Address for correspondence: Henry M. Kronenberg, Endocrine Unit, Massachusetts General Hos-
pital, Thier 501, 50 Blossom St., Boston, MA 02114. Voice: 617-726-3966; fax: 617-726-7543.
Ann. N.Y. Acad. Sci. 1068: 1–13 (2006). C ?2006 New York Academy of Sciences.
2 ANNALS NEW YORK ACADEMY OF SCIENCES
exhibit a variety of actions ranging from relaxation of many smooth muscle
notypes of mice missing the PTHrP gene,3the PTH/PTHrP receptor gene,4
and the PTH gene.5The mice missing PTHrP die at birth because all bones
formed by endochondral bone formation develop improperly.6,7As a result,
the rib cage is small and inappropriately mineralized, leading rapidly to death.
Further studies have shown that PTHrP regulates the proliferation and differ-
entiation of growth plate chondrocytes. These actions typify local actions of
PTHrP in many organs. The similarities of the growth plates of PTHrP (−/−)
mice and those of PTH/PTHrP receptor (−/−) mice bring genetic support for
the idea that the PTH/PTHrP receptor mediates the actions of PTHrP on the
growth plate. Here I will review the actions of PTHrP in the growth plate,
the way that PTHrP signaling is coordinated with signaling in other pathways,
and initial genetic studies that explore the intracellular mechanisms of PTHrP
ENDOCHONDRAL BONE FORMATION
The development of all bones begins with the formation of mesenchymal
condensations. Groups of mesenchymal cells draw close together and initiate
a characteristic genetic program. In a few bones, such as the flat bones of
the skull, these condensations then differentiate directly into osteoblasts. In
most bones, however, mesenchymal cells differentiate into chondrocytes and
an adjacent perichondrium. The chondrocytes then direct the differentiation
of perichondrial cells into osteoblasts, through a process called endochondral
bone formation.8FIGURE 1 illustrates the steps in endochondral bone forma-
round chondrocytes (FIG. 1C). These chondrocytes proliferate and secrete a
matrix rich in collagen type II and aggrecan. In response to a still unknown
signal, chondrocytes in the middle of the developing bone stop proliferating,
enlarge (hypertrophy), and change their genetic program to secrete a matrix
the mineralization of the surrounding matrix, signal to adjacent perichondrial
cells to direct their differentiation into osteoblasts, and also stimulate the in-
vasion of blood vessels. With vascularization, preosteoblastic cells from the
perichondrial region also invade the cartilage to begin formation of the first
true bone inside the cartilage mold called the primary spongiosa (FIG. 1E,F).
Osteoclasts, cells derived from the hematopoietic lineage, also enter the car-
tilage mold and, together with the cells of the osteoblastic lineage, digest the
matrix that had been synthesized by the hypertrophic chondrocytes. These
chondrocytes die through apoptosis at the border of the cartilage and primary
spongiosa. At the ends of the cartilage mold, round chondrocytes continue to
12ANNALS NEW YORK ACADEMY OF SCIENCES
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