Phone: (215) 898-6569
Fax: (215) 898-3695
Position: Professor & Chair
The overall goal of my research program is to define the regulated expression of genes encoding extracellular matrix proteins during differentiation and development. As a model, my laboratory has chosen to examine the control of collagen gene expression i n differentiating chondrocytes. Preschondrogenic mesenchymal cells synthesize an extracellular matrix comprised largely of types I and III collagen. As these cells differentiate into cartilage producing chondrocytes, they cease synthesis of types I and III collagen and initiate synthesis of type II and other cartilage specific collagens. In cartilages destined to be replaced by bone, the chondrocytes undergo hypertrophy, a process of further maturation, during which type II collagen is replaced by a unique collagen, type X. My laboratory is investigating several aspects of extracellular matrix gene expression during chondrogenesis and hypertrophy, as outlined below.
One research project examines the regulation of the type III collagen gene during skeletal development. Type III collagen is present in prechondrogenic mesenchyme, but disappears during chondrogenesis and is not found in embryonic cartilages. However, it reappears in adults in articular cartilage and in the intervertebral disc, perhaps in response to compression or other stress; furthermore, it is induced focally in osteoarthritis. We propose to examine the ability of compression to induce type III collagen gene expression in chondrocytes. In addition, the role of type III collagen in the skeleton is being examined using mice in which are haploinsufficient for type III collagen; in addition, we propose to overexpress type III collagen in cartilages of transgenic mice, and examine the effects on skeletal morphology and biomechanical properties.
In a related project, we discovered that the chick type III collagen gene contains an internal promoter within intron 23 (over 20 kb downstream of the previously characterized promoter). This promoter is active in cultured chondrocytes, but not in fibroblastic cells; we have identified the DNA sequences and transcription factors that give rise to the cell type-specific function this promoter. In addition, we have shown that the alternative transcript arising from use of the internal promoter is translated to produce a unique noncollagenous protein. The protein is encoded within exons 25-34 of the type III collagen gene, but uses an alternative reading frame. This novel protein is found in embryonic cartilage, bone and muscle. Thus the type III collagen gene is one of only a handful of eukaryotic genes that encode two unrelated proteins within the same exons.
Finally, the hypertrophic cartilage matrix is the site of cartilage calcification, which precedes endochondral bone formation. My laboratory, in collaboration with the laboratory of Dr. Phoebe Leboy, is using an in vitro chondrocyte maturation system which closely mimics the in vivo maturation process, to examine the signals that activate the type X collagen gene during chondrocyte hypertrophy. We are particularly interested in the interplay of retinoids, thyroid hormone and bone morphogenetic proteins (BMPs) in activation of this process. Cultured chondrocytes treated with any one of these agents accelerate their rate of maturation and prematurely induce type X collagen gene expression. Retinoids dramatically stimulate BMP production, indicating that retinoids act in part through a BMP-dependent mechanism. In addition, we have identified a retinoid-responsive region of the promoter which is BMP-independent. Our current experiments are focused on dissecting the crosstalk between these three signaling pathways.
1. Bennett, V.D., Weiss, I.M. and ADAMS, S.L.
Cartilage-specific 5' end of chick a2(I)collagen
mRNAs. J. Biol. Chem. 264:8402-8409, 1989.
2. Bennett, V.D. and ADAMS, S.L. A cartilage-specific promoter within intron 2 of the chick a2(I) collagen gene. J.Biol. Chem. 265:2223-2230, 1990.
3. ADAMS, S.L., Pallante, K.M., Niu, Z., Leboy, P.S., Golden, E.B. and Pacifici, M. Rapid induction of type X collagen gene expression in cultured chick
vertebral chondrocytes. Exp. Cell Res. 192:190-197, 1991.
4. Bennett, V.D., Pallante, K.M. and ADAMS, S.L. The splicing pattern of fibronectin mRNA changes during chondrogenesis, resulting in an unusual form of
the mRNA in cartilage. J. Biol. Chem. 266:5918-5924, 1991.
5. Pacifici, M., E.B. Golden, M. Iwamoto and ADAMS, S.L. Retinoic acid treatment induces type X collagen gene expression in cultured chick chondrocytes.
Exp. Cell Res. 195:38-465, 1991.
6. Iwamoto, M., Golden, E.B., ADAMS, S.L., Noji, S. and Pacifici, M. Responsiveness to retinoic acid changes during chondrocyte maturation. Exp. Cell
Res. 205:213-224, 1993.
7. Iwamoto, M., Shapiro, I.M., Yagami, K., Boskey, A.L., Leboy, P.S., ADAMS, S.L. and Pacifici, M. Retinoic acid induced rapid mineralization and
expression of mineralization-related genes in chondrocytes. Exp. Cell Res. 207:413-420, 1993.
8. Nah, H-D., Niu, Z. and ADAMS, S.L. An alternative transcript of the chick type III collagen gene that does not encode type III collagen. J. Biol. Chem.
9. Pallante, K.M., Niu, Z., Zhao, Y., Cohen, A.J., Nah, H.D., and ADAMS, S.L. The chick a2(I) collagen gene contains two functional promoters, and its
expression in chondrocytes is regulated at both transcriptional and post-transcriptional levels. J. Biol. Chem. 271:25233-25239, 1996.
10. Nah, H.D., Bennett, V.D., Niu, Z. and ADAMS, S.L. Alternative transcript of the chick a2(I) collagen gene is transiently expressed during endochondral
bone formation and during development of the central nervous system. Devel. Dynam. 206:146-158, 1996.
11. Zhang, Y., Niu, Z., Cohen, A.J., Nah, H.D. and ADAMS, S.L. The chick type III collagen gene contains two promoters that are preferentially expressed in
different cell types and are separated by over 20 kb of DNA containing 23 exons. Nucleic Acids Research 25:2470-2477, 1997.
12. Kirsch, T., Nah, H.D., Demuth, D.R., Harrison, G., Golub, E.E., ADAMS, S.L. and Pacifici, M. Annexin V-mediated calcium flux across membranes is
dependent on the lipid composition: Implications for cartilage mineralization. Biochemistry 36:3359-3367, 1997.
13. Zhang, Y., Z. Niu, C. Kelly, A. J. Cohen, H.-D. Nah and S. L. ADAMS: The chick type III collagen gene contains two cell type-specific promoters
separated by at least 20 kb of DNA containing 23 exons. Nucleic Acids Res. 25, 2470-2477, 1997.
14. Koyama, E., E. B. Golden, T. Kirsch, S. L. ADAMS, R. A. S. Chandraratna, J.-J. Michaille and M. Pacifici: Retinoid signaling is required for chondrocyte
maturation and endochondral bone formation during limb skeletogenesis. Dev. Biol. 208, 375-391, 1999.
15. Zhang, Y., Z. Niu, A. J. Cohen and S. L. ADAMS: The internal chondrocyte-specific promoter of the chick type III collagen gene is activated by AP1 and
is repressed in fibroblasts by a complex containing an LBP1-related protein. Nucleic Acids Res. 27, 4090-4099, 1999.
16. Nah, H.-D., M. Pacifici, L. C. Gerstenfeld, S. L. ADAMS and T. Kirsch: A transient chondrogenic phase in intramembranous pathway during normal
skeletal development. J. Bone Min. Res. 15, 522-533, 2000.
17. Leboy, P. S., G. Grasso-Knight, M. D'Angelo, S. W. Volk, J. B. Lian, H. Drissi, G. S. Stein and S. L. ADAMS: Smad-Runx interactions during
chondrocyte maturation. J. Bone Joint Surg. 83A, S1-S15, 2001.
18. Cohen, A. J., T. R. Lakshmi, Z. Niu, J. Trindade, P. C. Billings and S. L. ADAMS: A novel noncollagenous protein encoded by an alternative transcript
of the chick type III collagen gene is expressed in cartilage, bone and muscle. Mech. Dev. 114, 177-180.
19. ADAMS, S. L., K. M. Pallante, Z. Niu, A. J. Cohen, J. Lu and P. S. Leboy: Stimulation of type X collagen gene transcription by retinoids occurs in part
through the BMP signaling pathway. J. Bone Joint Surg., 2003 in press.