Abstract 2005 MHE Conference

Henry M. Kronenberg M.D.,PH.D.
Endocrine Unit, Massachusetts General Hospital and
Harvard Medical School, Boston, MA 02114

Chondrocytes in the growth plate are the engine that causes bone lengthening.  Chondrocytes proliferate and secrete matrix.  
They then stop proliferating, enlarge several fold (hypertrophy), mineralize the matrix surrounding them, and then die. The
matrix remaining provides a scaffold for subsequent formation of bone by osteoblasts.

To assure a proper balance between chondrocyte proliferation and hypertrophy, elaborate regulatory mechanisms have evolved.
 Parathyroid hormone-related protein (PTHrP), a relative of the calcium-regulating hormone, parathyroid hormone, is secreted by
perichondrial cells and chondrocytes at the ends of long bones of the limb.  

PTHrP acts to keep chondrocytes proliferating, thereby allowing the generation of more chondrocytes and delaying the onset of
chondrocyte hypertrophy.  Only when chondrocytes bearing receptors for PTHrP are sufficiently far from a source of PTHrP do
the chondrocytes then stop proliferating.  

PTHrP works by activating a receptor of the G protein-coupled receptor family.  Activation stimulates the heterotrimeric G
protein, Gs; this activation leads to generation of cyclic AMP and activation of protein kinase A.  These processes lead to
suppression of the cell cycle inhibitor, p57, and also suppression of the expression of the transcription factor, Runx2.  
Suppression of p57 is a major mechanism that results in the continued proliferation of chondrocytes.  Since Runx2 is a major
inducer of chondrocyte hypertrophy, the suppression of Runx2 expression by PTHrP also contributes to the continued
proliferation and delay of hypertrophy of chondrocytes.

As chondrocytes stop proliferating, they begin secreting Indian hedgehog. Indian hedgehog (Ihh) has multiple roles in regulating
the growth plate.  Ihh stimulates the synthesis of PTHrP, a role that then leads to further expansion of the layers of
proliferating chondrocytes.  

Since these proliferating chondrocytes do not synthesize Ihh, the stimulation of PTHrP synthesis by Ihh serves to negatively
regulate the expression of Ihh.  Ihh also accelerates the conversion of round chondrocytes, found at the top of the growth
plate, into flat columnar chondrocytes.  Since the flat columns formed by these cells align in the primary axis of growth of the
growth plate, this action of Ihh serves to help determine the final length and shape of the bones.  Ihh also stimulates the
proliferation of chondrocytes and acts on adjacent perichondrial cells to convert them to osteoblasts.  Thus, Ihh is a master
regulator of the growth plate which controls chondrocyte proliferation and differentiation, as well as the differentiation of
adjacent osteoblasts.  
Henry Kronenberg, research focuses on the regulation of bone and mineral metabolism and bone development. Particular
emphasis is placed on parathyroid hormone, parathyroid hormone-related protein, and vitamin D. The work includes both clinical
investigation, as exemplified by the Specialized Center for Research in Osteoporosis, funded by NIH, which is conducting a trial
of parathyroid hormone therapy for osteoporosis, and fundamental molecular research, such as studies of the mechanisms of
action of the PTH/PTHrP receptor. Bone development is studied through the creation of a series of gene "knockout" mice.

Dr. Kronenberg serves on the Scientific and Medical Advisory Board of the MHE Research Foundation and was past
president 1993-1994 of th
e The American Society for Bone and Mineral Research (ASBMR) & currently the Vice President
of International Bone and Mineral Society (
IBMS)
Research authored by Dr. Kronenberg
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List of Publications via PubMed
(NIH National Library of Medicine)
Dr. Kronenberg's research
How PTHrP regulates chondrocytes in the growth plate
Video presentation link of Dr. Kronenberg's presentaton during the ASBMR conference held on September 2006

The MHE Research would like to thank ASBMR for the use of the presentation on the MHE Research Foundation
website.
To view this video presentation given by Dr. Henry Kronenberg during this conference please click the link tab
For more detailed information concerning the Perichondrium, chondrocytes,  PTHrP, Ihh  and other signaling
pathways affected in by the defect in the EXT genes please view the video.

April 25–28, 2007, the 2nd Conference on Skeletal Biology and Medicine held in NYC.
This meeting, was jointly hosted at the New York Academy of Sciences and Mount Sinai School of Medicine,
was
organized and chaired by Mone Zaidi, professor of endocrinology, geriatrics and adult development, and structural and chemical
biology at Mount Sinai. Cochairs were Gerard Karsenty of Columbia University and Steven Teitelbaum of the Washington
University School of Medicine.

The MHE Research would like to thank all for the use of the presentation on the MHE Research Foundation website.
To view this video presentation given by Dr. Henry Kronenberg during this conference please click the link tab
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2009 Conference abstract
PTH/PTHrP Receptor Signaling is Required for Maintenance of the Growth Plate in Postnatal Life

Takao Hirai1, Andre S. Chagin1, Susan Mackem2, Tatsuya Kobayashi1, and H. M. Kronenberg1
1Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA and 2National Institutes of
Health, Bethesda, MD, USA.

PTHrP (PTHrP), regulated by Indian hedgehog (Ihh) and acting through the PTH/PTHrP receptor (PPR) is crucial for normal
cartilage development. These observations suggest a possible role for PPR signaling in the postnatal growth plate; however, the
role of PPR signaling in postnatal chondrocytes is unknown, because embryonic lethality of PPR null mice does not allow
examination of the physiological role of PPR signaling in postnatal chondrocytes. To overcome this issue, we have generated
tamoxifen-inducible and conditional Coll2-CreERt:floxed PPR (PPRfl/fl)-knockout mice to allow such postnatal analysis.

To generate Coll2-CreERt:PPRfl/fl mice, we crossed Coll2-CreERt:PPRfl/fl mice to PPRfl/fl miceColl2-CreERt:PPRfl/fl and PPRfl/fl
control mice were treated with single dose of 0.5 mg tamoxifen per body at postnatal day (P)3, and the effects on bone
development were analyzed at P6, P7 and P10. Three days after treatment of tamoxifen, the columns of chondrocytes in the
growth plate were disrupted, and the region of hypertrophic chondrocytes expressing collagen X was greatly expanded into the
middle of the growth plate. Furthermore, histological analysis of tibia of P10 showed that the premature closure of the growth
plate had already occurred in Coll2-CreERt:PPRfl/fl mice. To test the possibility that the deletion of PPR signaling could affect cell
death of chondrocytes, we performed the TUNEL assay and immunohistochemistry for cleaved caspase-3 in growth plates.  We
observed ectopic TUNEL and activated caspase 3 positive cells in the columnar region of growth plate chondrocytes, along with
an increase in apoptotic cells at the end of the hypertrophic layer of Coll2-CreERt:PPRfl/fl at 4 days after tamoxifen
administration. Simultaneous administration of a low phosphate diet, that prevents apoptosis of late hypertrophic chondrocytes
in normal growth plates, prevented the disappearance of the growth plate after tamoxifen administration.

These results suggest that activation of the PPR is required for continued survival of chondrocytes in the postnatal growth
plate. Postnatal ablation of PPR in chondrocytes results in premature closure of the growth plates and permanent deformity of
bone epiphyses. Moreover, chondrocyte apoptosis through the activation of a caspase 3 pathway may be involved in the
process of growth plate closure by postnatal deletion of PPR in chondrocytes.
Photo's taken during the
Third International MHE Research Conference










































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