CCN proteins in the musculoskeletal system: current understanding and challenges in physiology and pathology

Abstract

The acronym for the CCN family was recently revised to represent “cellular communication network”. These six, small, cysteine-enriched and evolutionarily conserved proteins are secreted matricellular proteins, that convey and modulate intercellular communication by interacting with structural proteins, signalling factors and cell surface receptors. Their role in the development and physiology of musculoskeletal system, constituted by connective tissues where cells are interspersed in the cellular matrix, has been broadly studied. Previous research has highlighted a crucial balance of CCN proteins in mesenchymal stem cell commitment and a pivotal role for CCN1, CCN2 and their alter ego CCN3 in chondrogenesis and osteogenesis; CCN4 plays a minor role and the role of CCN5 and CCN6 is still unclear. CCN proteins also participate in osteoclastogenesis and myogenesis. In adult life, CCN proteins serve as mechanosensory proteins in the musculoskeletal system providing a steady response to environmental stimuli and participating in fracture healing. Substantial evidence also supports the involvement of CCN proteins in inflammatory pathologies, such as osteoarthritis and rheumatoid arthritis, as well as in cancers affecting the musculoskeletal system and bone metastasis. These matricellular proteins indeed show involvement in inflammation and cancer, thus representing intriguing therapeutic targets. This review discusses the current understanding of CCN proteins in the musculoskeletal system as well as the controversies and challenges associated with their multiple and complex roles, and it aims to link the dispersed knowledge in an effort to stimulate and guide readers to an area that the writers consider to have significant impact and relevant potentialities.

CCN proteins: opportunities for clinical studies—a personal perspective

“…This is a recurring theme voiced by many reviewers in the field. Giusti & Scotlandi (2021) in their comprehensive review configured a diagram outlining the consequences of knocking out ccn1-6 in mice in terms of general phenotype and skeletal phenotype. In comparison (and contrast) to ccn1-3 no general phenotypic and skeletal phenotypes were reported for CCN 4, 5 and 6.…”

The role of CCNs in controlling cellular communication in the tumor microenvironment

“…CCN1 is a secreted matricellular protein with a molecular mass of 40 kDa (Banerjee et al 2016; Giusti and Scotlandi 2021). The prototypic CCN1 protein is encoded by the inducible immediate‐early gene and is activated by and further enhances growth and mechanical factors (Babic et al 1998; Kim et al 2018b).…”

Inception and establishment of the International CCN Society (ICCNS) and of the Journal of Cell Communication and Signaling (JCCS): A response to A. Leask’s Editorial entitled "Modeling the microenvironment special issue"

“…This present response highlights key references, taken among the 154 reviews and 1255 articles citing CCN on PubMed: Brigstock,1999; Brigstock et al 2003, Bork 1993; Birkeness, 2022; Giusti and Scotlandi 2021; Joliot et al 1992; Krupska et al 2015; Kubota et al 2022; Lau and Lam 1999; Lau 2016; Perbal 1994; Perbal 2001; Perbal 2004; Perbal 2013; Perbal and Perbal 2016; Perbal 2018; Perbal et al 2018; Tran 2018; Twigg 2018; Weiskirchen 2011; Yeger and Perbal 2021). Notably, this wealth of scientific achievements and contribution to the scientific literature has rested on the initial efforts made by those recognized herein who established the ICCNS and JCCS.…”