**4. Bone remodeling (bone turnover) shift**

Orthopedic infection and excessive production of pro-inflammatory cytokines [15] influence the bone remodeling balance. Such hyperproduction can be triggered by infection itself and can increase when the pathogen persists inside the osteoblasts. Furthermore, some pathogens can additionally increase the inflammatory response because of paracrine action of their factors, interfering with the cytokine balance [26]. As it will be shown later, the inflammatory response tends to turn into a hyperergic response because of excessive activation of the cell immunity, which is an important factor for chronization of the process.

One of the most well-studied bacterial pathogens that is convenient for illustration is *S. aureus*. Many authors [14, 15, 27] show that *S. aureus* influences both parts of the bone turnover-bone resorption and ossification. During infection, *S. aureus* not only destroys (damages) osteoblasts through necrosis and apoptosis, but also lowers their proliferation rate. Influence on bone resorption is based on rapid maturation and additional activation of the osteoclasts by this pathogen. This mechanism is based on excessive synthesis of prostaglandin Е2 (PGE2) by osteoblasts and persisting of *S. aureus* inside the osteoblasts, as well as auto and paracrine regulatory mechanisms in which PGE2 plays its biochemical role. The synthesis of osteoprotegerin (OPG) is also impaired because of lowering of the level of corresponding mRNA; [28] as a result, more RANK-ligand (RANKL) molecules remain unbound and act as osteoclast activators. Excessive activation of the osteoclasts and lowering of the number and proliferation rate of the osteoblasts lead to obvious shift of the bone turnover to bone resorption. As a result, the loss of bone tissue and impairment of its mineralization at the site of orthopedic infection (bone infection) can lead to difficulties in bone consolidation in patients with bone defects and/or fractures (**Figure 3**).

"Red blocks" of this part include the OPG and RANK-ligand (RANKL) level changes.

"Yellow blocks" include the pre-existing low level of the osteoprotegerin. An example is a case of chronic osteomyelitis development in a patient with preexisting low-speed bone turnover and associated osteoporosis with OPG synthesis impairment.

These markers are rarely used in routine clinical practice but can be of a certain value when an appropriate laboratory is available.

*Clinical Implementation of Bone Regeneration and Maintenance*

destruction of osteoblasts.

**3. Osteoblast cell death and proliferation lowering**

One of the most obvious effects of bacterial pathogen on a bone tissue is the

Destruction of osteoblasts includes necrotic and apoptotic pathways. Papers contributing to the study of *S. aureus'* influence on the osteoblast culture show that these two pathways work independently. Apoptosis is triggered by ligand TRAIL

*Pathogenetic stages and processes associated particularly with osteoblast cell death and proliferation lowering. The link between bone matrix destruction processes and associated decrease in osteoblast proliferation rate (will* 

*be shown and illustrated in the corresponding part of the chapter).*

**140**

**Figure 2.**

#### **Figure 3.**

*Pathogenetic stages and processes associated particularly with bone turnover shift.*

OPG is a soluble glycoprotein synthesized by different cell types, including osteoblasts [29]. This compound can be found in monomeric (50 kDa) or dimeric (120 kDa) form (the dimeric form contains disulfide bonds between monomers). Dimeric form has a higher affinity to RANKL than a monomeric one, and the chemical analogues of OPG should have the features of dimeric form.

RANKL (RANK-ligand) is a compound synthesized by several cell types. It can be expressed in three different molecular forms: transmembrane trimer, primary (secreted) form, and cell ectodomain [30]. RANKL serves as a ligand for RANK receptor that activates osteoclasts. RANKL is a target for osteoprotegerin; if OPG is secreted in low amounts, more RANKL remains unbound and the intensity of resorption increases.

Therefore, a "pathogenetic chain" is as follows: infection-osteoblast cell death and proliferation rate decrease-OPG synthesis decrease-RANKL inhibition decrease-osteoclastogenesis activation-bone resorption increase-shift of bone remodeling toward a resorption prevalence-decrease in bone tissue quality and quantity in the infection site. The resulting clinical effect is slowing of the consolidation of the bone tissue defects, pseudarthroses, and related conditions.

#### **5. Matrix destruction**

The matrix destruction in infection can be explained by several factors. The "starting point" in pathogenesis is the infection itself. *S. aureus* is, as shown by

**143**

**Figure 4.**

*Metabolic Disorders in Patients with Chronic Osteomyelitis: Etiology and Pathogenesis*

several authors [14, 31, 32], capable of persisting in osteoblasts and that leads to additional stimulation of inflammatory process that stepwise turns into local hyperergic reaction. It is important to take into account that pathogens also play a role in matrix destruction—particularly *S. aureus* can adhere to matrix elements and

The hyperergic reaction leads to excessive synthesis of matrix metalloproteases (MMPs). Among them, MMP-2 (gelatinase A) and MMP-9 (gelatinase B) [34] play the main role. Excessive synthesis of MMP is a key point in the process because it

• Osteoblast cell death and lowering of the proliferation rate; this effect weakens

• MMPs damage the matrix by themselves, being synthesized in excessive

*Pathogenetic stages and processes associated particularly with bone matrix destruction.*

*DOI: http://dx.doi.org/10.5772/intechopen.92052*

the regenerative potential of bone tissue.

destroy them [33].

has two major effects:

amounts [34, 35].
