Table 1 Top upregulated (green) and downregulated proteins (red) in d14-CM compared to regular CM and their presence as hub proteins in string network of functional associations

HSPG2 - perlecan

69

d14 CL2

Ubiquitous matrix stabilizing proteoglycan Roles in angiogenesis, connective tissue development and repair

[42]

LASP1 -

LIM and SH3 protein 1

50

d14 CL1

Ubiquious LIM subfamily signaling protein, overexpressed in cancer cells

Binds to actin cytoskeleton; has a role in embryonic development

[43]

IGFBP7 - insulin-like growth factor binding protein 7

42

d14 CL2

Member of IGF-binding protein family

Induces osteogenic differentiation of bone marrow-derived MSCs

[44]

LOXL2 – lysyl oxidase like 2

33

d14 CL2

Member of lysyl oxidase family

Catalyzes cross links in collagen and elastin

[45]

HTRA1 - HtrA serine peptidase 1

24

Member of serine protease family

Regulates availability of IGF-like growth factors

[46]

THBS2 – thrombospondin 2

24

d14 CL2

Member of thrombospondin family

Mediates cell-cell and cell-matrix interactions, influences bone fracture healing

[47, 48]

PDIA3 - protein disulfide isomerase family A member 3

24

Ubiquious endoplasmic reticulum protein

Modulates protein folding, involved in production of ECM

[49, 50]

VCAN - versican

21

d14 CL2

Member of aggrecan/versican proteoglycan family, major component of ECM

Involved in cell adhesion, proliferation, migration, angiogenesis

[51]

SPARC - secreted protein acidic and cysteine-rich

20

d14 CL2

ECM protein involved in matrix synthesis, and cell shape changes

Required for bone collagen calcification

[52]

BGN - biglycan

15

d14 CL2

Member of small leucine-rich proteoglycan family of proteins

Role in bone growth, muscle development and regeneration, and collagen fibril assembly in multiple tissues

[53]

FBN1 – fibrillin 1

12

d14 CL2

Extracellular matrix glycoprotein

Component of calcium-binding microfibrils that provide structural support in connective tissue

[54]

IGFBP2 – insulin growth factor binding protein 2

11

d14 CL2

One of six proteins binding insulin growth factors

Promotes tumor growth, role in regulation of bone metabolism

[55, 56]

NPM1 - nucleophosmin 1

-20

CL1

Invovled in centrosome duplication, protein chaperoning, and cell proliferation

Sequesters tumor supressor ARF

[57]

STMN1- stathmin 1

-14

Member of stathmin family

Intracellular relay for signals of the cellular environment, regulates cell proliferation, destabilizes microtubules

[58]

RPL12 - ribosomal protein L12

-11

Component of the 60 S ribosomal subunit

Binds directly to 26 S rRNA

[59]

PTX3 - pentraxin 3

-11

Member of pentraxin protein family

Induced by inflammatory cytokines, plays a role in angiogenesis and tissue remodeling

[60]

PCOLCE - procollagen C-endopeptidase enhancer

-10

CL2

Ubiquious glycoprotein

Mediates enzymatic cleavage of type I procollagen, heightens C-proteinase activity

[61]