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Perlecan/HSPG2: Signaling role of domain IV in chondrocyte clustering with implications for Schwartz‐Jampel Syndrome
Author(s) -
Martinez Jerahme R.,
Grindel Brian J.,
Hubka Kelsea M.,
Dodge George R.,
FarachCarson Mary C.
Publication year - 2019
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.27521
Subject(s) - perlecan , aggrecan , chondrocyte , microbiology and biotechnology , cartilage oligomeric matrix protein , chondrogenesis , chemistry , proteoglycan , type ii collagen , signal transduction , cartilage , extracellular matrix , biology , anatomy , medicine , osteoarthritis , pathology , alternative medicine , mesenchymal stem cell , articular cartilage
Perlecan/heparan sulfate proteoglycan 2 (HSPG2), a large HSPG, is indispensable for the development of musculoskeletal tissues, where it is deposited within the pericellular matrix (PCM) surrounding chondrocytes and disappears nearly completely at the chondro‐osseous junction (COJ) of developing long bones. Destruction of perlecan at the COJ converts an avascular cartilage compartment into one that permits blood vessel infiltration and osteogenesis. Mutations in perlecan are associated with chondrodysplasia with widespread musculoskeletal and joint defects. This study elucidated novel signaling roles of perlecan core protein in endochondral bone formation and chondrocyte behavior. Perlecan subdomains were tested for chondrogenic properties in ATDC5 cells, a model for early chondrogenesis. A region within domain IV of perlecan (HSPG2 IV‐3) was found to promote rapid prechondrocyte clustering. Introduction of the mutation (R3452Q) associated with the human skeletal disorder Schwartz‐Jampel syndrome limited HSPG2 IV‐3‐induced clustering. HSPG2 IV‐3 activity was enhanced when thermally unfolded, likely because of increased exposure of the active motif(s). HSPG2 IV‐3‐induced clustering was accompanied by the deactivation of key components of the focal adhesion complex, FAK and Src, with increased messenger RNA (mRNA) levels of precartilage condensation markers Sox9 and N‐cadherin ( Cdh2 ), and cartilage PCM components collagen II ( Col2a1 ) and aggrecan ( Acan ). HSPG2 IV‐3 reduced signaling through the ERK pathway, where loss of ERK1/2 phosphorylation coincided with reduced FoxM1 protein levels and increased mRNA levels cyclin‐dependent kinase inhibitor 1C (Cdkn1c) and activating transcription factor 3 ( Atf3 ), reducing cell proliferation. These findings point to a critical role for perlecan domain IV in cartilage development through triggering chondrocyte condensation.