CONSTITUTIVE EXPRESSION OF PARATHYROID HORMONE-RELATED PEPTIDE (PTHRP) STIMULATES GROWTH AND INHIBITS DIFFERENTIATION OF CFK2 CHONDROCYTES

We have examined the effects of constitutive expression of PTHrP on th e growth and differentiation of populations of cells derived from a cl onal chondrocytic cell line, CFK2. Cells were stably transfected with cDNA encoding either full-length, secretory PTHrP (CFK2P) or nonsecret ory PTHrP (CFK2P-SS). In cultures of cells plated at low density, secr etory PTHrP acted as a potent mitogen compared with nonsecretory PTHrP or exogenous PTHrP-(1-34), both of which stimulated only a minor incr ease in proliferation. In populations of control cells maintained post confluent for several weeks, there was a dramatic increase in expressi on of mRNA for type II collagen, aggrecan, and link protein. Addition of exogenous PTHrP-(1-34) at a concentration of 10(-8) M to these cult ures was ineffective in inhibiting this time-dependent increase in exp ression of matrix proteins. In contrast, populations of cells producin g either secretory or nonsecretory forms of PTHrP, maintained over the same time period, demonstrated an almost complete inhibition of mRNA expression for matrix proteins. These observations demonstrate that PT HrP acts as a bifunctional modulator of chondrogenesis and that some o f its biological activity is exerted via a mechanism distinct from the recognised signal transduction pathways linked to the PTH/PTHrP recep tor. (C) 1996 Wiley-Liss, Inc.