**3. Other growth factors that affect longitudinal growth: C-type natriuretic peptide**

C-type natriuretic peptide NP is anabolic in the growth plate, articular cartilage, and in bone tissue: We and others have shown that CNP is anabolic in the growth plate and that CNP/ natriuretic peptide receptor-B (NPR-B)/cyclic guanosine monophosphate (cGMP) signaling regulates linear bone growth/endochondral bone formation through the cGMP-dependent protein kinase II (cGK-2). CNP induces chondrocyte proliferation, differentiation, and extracellular matrix (ECM) production.

We have recently shown that transgenic mice that overexpress CNP under the control of the type-II collagen promoter had increased endochondral bone growth with thick and matrix-rich articular joint cartilage. Most importantly, we have also shown that in an animal model of inflammatory arthritis, CNP overexpression in chondrocytes protects the articular cartilage integrity and prevents subchondral bone defects [27]. Our transgenic mice that overexpressed CNP on cartilage developed dense trabeculation under the subchondral bone supporting in vitro experiments showing increased matrix secretion by osteoblastic cells [44]. In addition, there is data about CNP enhancing ECM secretion in cultured articular chondrocytes seeded on a type-II collagen-coated scaffold [45]. CNP has a unique dual anabolic effect on chondrocytes and osteoblasts for matrix synthesis. Together, these findings suggest that CNP is an ideal growth factor to be used in TE for osteochondral defects since it may promote both cartilage and bone regeneration.

CNP improves vasculogenesis and graft survival: Vascular endothelial cells also express and secrete CNP, and CNP has a major role in embryonic vasculogenesis and graft vasculogenesis [46, 47].

Angiogenesis is essential for bone formation during embryonic life and after fracture, indicating a further role in bone fracture healing for CNP.
