**6. CNP's role in vascular homeostasis**

with increased proteoglycan deposition as evidenced by strong Safranin-O staining [27]. CNPcol2a1TG mice developed increased endochondral bone growth (30%) and developed kyphosis due to vertebral overgrowth by 18 weeks (**Figure 2**). In the skeletal histomorphology of CNPcol2a1TG mice, the most intriguing finding was the increased trabecular bone formation in proximity to the growth plate cartilage, subchondral (juxta-articular) bones, and

C-type natriuretic peptide (CNP) has dual anabolic effects on cartilage and bone tissues. We have recently shown that CNP is a major contributor to post-natal skeletal growth in humans by its effects on the growth plate cartilage [58]. CNP also has an anabolic effect on bone morphogenesis [59]. Previous reports of in vitro experiments suggest that the CNP signaling system is an autocrine/paracrine regulator of osteoblast growth and differentiation, and CNP

Although it is one of the major regulators of endochondral bone growth with its impact on cartilage tissue and its homeostatic role in the growing bone tissue, CNP's role in adult bone is unclear. Recent research in ewes (adult female sheep) showed that when estrogen was given CNP, content was increased the most in the estrogen-responsive trabecular bones (vertebrae and iliac bones) more than the longitudinal bones (tibia). The same study suggested that dexamethasone injections to ewes did not change the content of CNP in bone tissue, while plasma CNP peptides and bone alkaline phosphatase levels were significantly

Dwarf mice, that is. Npr2 knockout or Nppc KO, have not been reported for the lack of their bone mineral content or bone mineral density. Our observation in the CNPcol2a1TG mice that overexpressed CNP, particularly in the cartilage tissue, was that both vertebral bones and the metaphysis/epiphysis of long bones, around the growth plates, develop significantly increased trabeculation and mineralization [59, 62]. This may be because Nppc overexpression was more significant in the growth plate cartilage and somewhat in the joint cartilage in our CNPcol2a1TG mice. Others using different promoters that caused increased production of CNP (SAP-CNP-Tg mice) in serum showed the effect of CNP on bone turnover microcomputed tomography (CT) analysis revealed increased trabeculation and dense bones lumber vertebrae in contrast to long bones such as femur. However, the fracture model showed that there is increased bone turnover and fracture healing in the SAP-CNP-Tg mice even in long bones with less trabecular ratio. Bone histomorphometric analysis of the tibiae from SAP-CNP-Tg mice showed that stabilized femoral fracture healing is advanced in SAP-CNP-Tg mice supporting the hypothesis that CNP regulates bone homeostasis and contributes to

Osteoblastic cell culture experiments showed CNP's anabolic effect in osteoblastic activity.

in vertebrae.

54 Newest Updates in Rheumatology

decreased.

remodeling [63].

**5. CNP's role in bone homeostasis**

plays a role in bone remodeling [60, 61].

One of the most important roles of CNP is in the venous system. CNP via its NPR2 a d NPR3 receptor signaling in the vascular wall regulates vasodilatation particularly on the venous wall. Enhanced osteoblastic and osteoclastic activities. In addition, serum levels of osteocalcin and tartrate-resistant acid phosphatase-5b, were elevated in the Tg mice. The same study showed that open and Vascular endothelial cells express and secrete CNP. CNP is suppressed by the VEGF secretion and is known to act as a vasodilator [64]. Also, CNP has been suggested to have a major role in angiogenesis [47, 65]. Once the growth plate is closed after puberty, the chondrogenic CNP will no longer available. Then CNP needed for trabecular bone remodeling will then have to be secreted partially by osteoblasts as a paracrine/autocrine factor and/ or by vascular endothelium. Steady serum levels of NT-proCNP may also be regulating the cartilage and bone homeostasis and the main source of NT-proCNP might only be the vascular endothelium. Due to the vascular wall expression of CNP and its vasodilator effect, CNP's role in hypertension, vasculitis and myocardial infarction has been studied.
