Lysyl oxidase-like-2 (LOXL2) is a major isoform in chondrocytes and is critically required for differentiation.
The lysyl oxidase family is made up of five members: lysyl oxidase (LOX) and lysyl oxidase-like 1-4 (LOXL1-LOXL4). All members share conserved C-terminal catalytic domains that provide for lysyl oxidase or lysyl oxidase-like enzyme activity; and more divergent propeptide regions. LOX family enzyme activities catalyze the final enzymatic conversion required for the formation of normal biosynthetic collagen and elastin cross-links. The importance of lysyl oxidase enzyme activity to normal bone development has long been appreciated, but regulation and roles for specific LOX isoforms in bone formation in vivo is largely unexplored. Fracture healing recapitulates aspects of endochondral bone development. The present study first investigated the expression of all LOX isoforms in fracture healing. A remarkable coincidence of LOXL2 expression with the chondrogenic phase of fracture healing was found, prompting more detailed analyses of LOXL2 expression in normal growth plates, and LOXL2 expression and function in developing ATDC5 chondrogenic cells. Data show that LOXL2 is expressed by pre-hypertrophic and hypertrophic chondrocytes in vivo, and that LOXL2 expression is regulated in vitro as a function of chondrocyte differentiation. Moreover, LOXL2 knockdown studies in vitro show that LOXL2 expression is required for ATDC5 chondrocyte cell line differentiation through regulation of SNAIL and SOX9, important transcription factors that control chondrocyte differentiation. Taken together, data provide evidence that LOXL2, like LOX, is a multifunctional protein. LOXL2 promotes chondrocyte differentiation by mechanisms that are likely to include roles as both a regulator and an effector of chondrocyte differentiation.
Department of Periodontology and Oral Biology, Henry M Goldman School of Dental Medicine, Boston University, Boston, Massachusetts 02118, USA.
Mussadiq
M
Iftikhar
Paola
P
Hurtado
Manish V
MV
Bais
Nate
N
Wigner
Danielle N
DN
Stephens
Louis C
LC
Gerstenfeld
Philip C
PC
Trackman
D000594:Amino Acid Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D019902:Chondrocytes / Q000166:cytology* / Q000201:enzymology*; D004195:Disease Models, Animal; D005109:Extracellular Matrix / Q000201:enzymology*; D017102:Fracture Healing / Q000502:physiology*; D050723:Fractures, Bone / Q000378:metabolism* / Q000473:pathology; D015971:Gene Expression Regulation, Enzymologic; D055785:Gene Knockdown Techniques; D006132:Growth Plate / Q000166:cytology / Q000502:physiology; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000378:metabolism
D007527:Isoenzymes; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D000594:Amino Acid Oxidoreductases; C485601:Loxl2 protein, mouse