Parathyroid hormone-related proteins is abundant in osteoarthritic cartilage, and the parathyroid hormone-related protein 1-173 isoform is selectively induced by transforming growth factor beta in articular chondrocytes and suppresses generation of extracellular inorganic pyrophosphate.
OBJECTIVE
Parathyroid hormone-related protein (PTHrP) is a major, locally expressed regulator of growth cartilage chondrocyte proliferation, differentiation, synthetic function, and mineralization. Because mechanisms that limit cartilage chondrocytes from maturing and mineralizing are diminished in osteoarthritis (OA), we studied PTHrP expression by articular chondrocytes.


METHODS
PTHrP was studied in normal knee cartilage samples and cultured articular chondrocytes, and in cartilage specimens from knees with advanced OA, obtained at the time of joint replacement.


RESULTS
PTHrP was more abundant in OA than in normal human knee articular cartilage. Both demonstrated PTH/PTHrP receptor expression. PTHrP 1-173, one of three alternatively spliced PTHrP isoforms, was exclusively expressed and induced by transforming growth factor beta in cultured chondrocytes. Chondrocytes mainly used the GC-rich P2 alternative promoter to express PTHrP messenger RNA. Inhibition by PTHrP 1-173, but not by PTHrP 1-146 or PTHrP 1-87, of inorganic pyrophosphate (PPi) elaboration suggested selective functional properties of the 1-173 isoform. Exposure to a neutralizing antibody to PTHrP increased PPi elaboration by articular chondrocytes.


CONCLUSIONS
Increased expression of PTHrP, including the 1-173 isoform, has the potential to contribute to the pathologic differentiated functions of chondrocytes, including mineralization, in OA.
Terkeltaub
R
R
San Diego Veterans Affairs Medical Center, University of California, 92161, USA.
Lotz
M
M
Johnson
K
K
Deng
D
D
Hashimoto
S
S
Goldring
M B
MB
Burton
D
D
Deftos
L J
LJ
D000328:Adult; D000368:Aged; D002131:Calcium Pyrophosphate / Q000378:metabolism*; D002358:Cartilage, Articular / Q000737:chemistry* / Q000166:cytology; D005110:Extracellular Space / Q000737:chemistry; D006801:Humans; D008875:Middle Aged; D010003:Osteoarthritis / Q000378:metabolism*; D044162:Parathyroid Hormone-Related Protein; D010446:Peptide Fragments / Q000096:biosynthesis* / Q000187:drug effects; D011401:Promoter Regions, Genetic; D020033:Protein Isoforms / Q000096:biosynthesis* / Q000187:drug effects / Q000494:pharmacology; D011506:Proteins / Q000378:metabolism*; D044168:Receptor, Parathyroid Hormone, Type 1; D018016:Receptors, Parathyroid Hormone / Q000032:analysis; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
C470121:PTHLH protein, human; D044162:Parathyroid Hormone-Related Protein; D010446:Peptide Fragments; D020033:Protein Isoforms; D011506:Proteins; D044168:Receptor, Parathyroid Hormone, Type 1; D018016:Receptors, Parathyroid Hormone; D016212:Transforming Growth Factor beta; C116787:parathyroid hormone-related protein (1-173); D002131:Calcium Pyrophosphate