Cartilage undergoes a multi-phase process of maturation during which chondrocytes proliferate, become hypertrophic, mineralize their matrix, and are replaced by bone. This cartilage maturation process is crucial for normal bone formation, postnatal growth and bone repair. Despite its obvious importance, little is known about the regulation of cartilage maturation. In the previous project, the hypothesis that vitamin A regulates the expression of type X collagen in maturing chondrocytes was examined in detail and, in the course of this work, strong evidence was found to support the idea that physiologic retinoids do not simply induce expression of one gene (collagen type X), but also cause expression of several maturation-related genes, matrix mineralization, and metabolic shifts in energy production. This complex sequence of events is precisely that occurring during the latter part of cartilage maturation in vivo, leading to the current proposal, an examination of the idea that retinoids induce the final phases of the chondrocyte maturation process. Since retinoids exert their biological functions by interactions with nuclear transcription factors, the retinoic acid receptors (RARs) and retinoid receptors (RXRs), and there is preliminary data to suggest that the expression of RARgamma is selectively activated in pre-hypertrophic and hypertrophic chondrocytes in the growth plate, in vivo, while immature resting and proliferating chondrocytes and articular chondrocytes do not express this receptor, this renewal proposes to study the expression and function of RARgamma in chondrocyte maturation. The central hypothesis to be tested is that the induction of the final phases of maturation by retinoids is mediated by RARgamma. Specifically, determination of the RARgamma isoform expressed during chondrocyte maturation, the regulation of RARgamma gene expression, the endogenous retinoids present in chondrocytes, and the function of RARgamma in chondrocytes will be addressed. The results of the proposed work are intended to provide crucial information on how retinoids and their nuclear receptors regulate cartilage maturation, and identify possible candidate mechanisms which may be affected during abnormal endochondral bone formation.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
Project #
Application #
Study Section
Orthopedics and Musculoskeletal Study Section (ORTH)
Program Officer
Sharrock, William J
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Pennsylvania
Anatomy/Cell Biology
Schools of Dentistry
United States
Zip Code
Kitagaki, J; Iwamoto, M; Liu, J-G et al. (2003) Activation of beta-catenin-LEF/TCF signal pathway in chondrocytes stimulates ectopic endochondral ossification. Osteoarthritis Cartilage 11:36-43
Iwamoto, M; Kitagaki, J; Tamamura, Y et al. (2003) Runx2 expression and action in chondrocytes are regulated by retinoid signaling and parathyroid hormone-related peptide (PTHrP). Osteoarthritis Cartilage 11:6-15
Enomoto-Iwamoto, M; Nakamura, T; Aikawa, T et al. (2000) Hedgehog proteins stimulate chondrogenic cell differentiation and cartilage formation. J Bone Miner Res 15:1659-68
D'Angelo, M; Yan, Z; Nooreyazdan, M et al. (2000) MMP-13 is induced during chondrocyte hypertrophy. J Cell Biochem 77:678-93
Yagami, K; Suh, J Y; Enomoto-Iwamoto, M et al. (1999) Matrix GLA protein is a developmental regulator of chondrocyte mineralization and, when constitutively expressed, blocks endochondral and intramembranous ossification in the limb. J Cell Biol 147:1097-108
Koyama, E; Golden, E B; Kirsch, T et al. (1999) Retinoid signaling is required for chondrocyte maturation and endochondral bone formation during limb skeletogenesis. Dev Biol 208:375-91
Kirsch, T; Nah, H D; Shapiro, I M et al. (1997) Regulated production of mineralization-competent matrix vesicles in hypertrophic chondrocytes. J Cell Biol 137:1149-60
Kirsch, T; Nah, H D; Demuth, D R et al. (1997) Annexin V-mediated calcium flux across membranes is dependent on the lipid composition: implications for cartilage mineralization. Biochemistry 36:3359-67
D'Angelo, M; Pacifici, M (1997) Articular chondrocytes produce factors that inhibit maturation of sternal chondrocytes in serum-free agarose cultures: a TGF-beta independent process. J Bone Miner Res 12:1368-77
Koyama, E; Shimazu, A; Leatherman, J L et al. (1996) Expression of syndecan-3 and tenascin-C: possible involvement in periosteum development. J Orthop Res 14:403-12

Showing the most recent 10 out of 14 publications