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Hypothesis on the Pathogenesis of Osteoarthritis

Osteoarthritic joint changes represent a common phenomenon that, given its progression, is difficult to treat. Accordingly, knowledge about the pathogenesis of osteoarthritis is important. This article compares the mechanism of secondary bone healing with that of osteoarthritis, and can show clear parallels based on numerous study findings. This leads to the hypothesis that osteoarthritis corresponds to a mechanism of bone healing in the wrong place.


Introduction
Degenerative joint changes are among the most common orthopedic diseases in humans and animals. As they progress, they can cause the complete destruction of the joint, including loss of function. Although there has been intensive research activity in this field, the findings on the pathogenesis of this disease are still incomplete.
The fact that joints ancylosis as a result of inactivity or final osteoarthritic changes, which creates a solid, bony connection between the articulated bones, and that, by contrast, insufficient bone healing after a fracture leads to pseudoarthrosis suggests that both mechanisms represent alternatives in bone and joint pathology.
It is these findings that gave rise to the hypothesis that the osteoarthritic joint changes reflect the organism's attempt to recreate a bony connection between the bone ends, pushed along by the mechanism of bone healing.

In Simpler Terms, Osteoarthritis is Bone healing in the Wrong Place!
The hypothesis is now to be demonstrated by comparative analyses of the mechanisms of bone healing and osteoarthritis. This involves looking at the phases of fracture healing with their biochemical and pathophysiological processes, and comparing them with osteoarthritis.

Bone healing consists of four phases
Inflammation, soft callus, hard callus and remodeling [1]. Depending on various factors, such as micro-movements which act during the healing phase, a distinction can be made between primary and secondary bone healing. According to the hypothesis, osteoarthritis would have to be a process equivalent to secondary bone healing.
In the following section, the phases of secondary bone healing will be compared with those of the pathogenesis of osteoarthritis The first phase: The first phase of bone healing begins immediately after the trauma event. It is the "inflammatory phase", initiated by tissue destruction and the fracture hematoma.
One can see destruction, bleeding and inflammatory cell infiltration in the affected tissue. In this phase of fracture healing, the concentration of proinflammatory cytokines, such as TNF-α, IL-1 and IL-6, increases in the fracture area [2][3][4]. Cytokines are secreted by macrophages and mesenchymal cells of the damaged tissue [5-6].
This release of these cytokines plays a key role in the further pathophysiological processes. For example, TNF-α induces the migration of mesenchymal stem cells to the fracture area and causes their metamorphosis into osteoblasts [5,7-9]. In the process, TNF-α acts via two receptor types, TNF-α Rec.1+2. Receptor 2 seems more significant for bone healing, which is underlined by the observation that progranulin, a growth factor of endochondral ossification, unfolds its effect in the development phase in relation to TNF-α Rec 2. [3,10].
IL-1 has a similar effect to TNF-α: it induces the endochondral bone formation by proliferating and differentiating preosteoblasts [11,12]. The growth-promoting effect of TNF-α and IL-1 is also reflected in the observation that TNF-α and IL-1 antagonists can suppress fracture healing [13]. The increased IL-6 concentration in a fracture area is seen as an indicator of its significance in connection with bone healing [14]. IL-6 increases osteoclastogenesis [15]. Tests on IL-6 knockout mice have shown that this is how IL-6 has a positive effect on callus mineralization In summary, the function of proinflammatory cytokines in the early phase of fracture healing consists of attracting mesenchymal stem cells to the fracture area and, once there, inducing their differentiation into osteoblasts and subsequent mineralization.
During the osteoarthritic joint remodeling, there is also an increased secretion of proinflammatory cytokines. Under the influence of IL-1 and TNF-α, IL-6 is formed by macrophages, chondrocytes, osteoblasts and adipocytes. [29,32-33] IL-6 acts via a receptor, and shows the same effects as IL-1 and TNF-α in the osteoarthritic joint with respect to reduced collagen production and synthesis of metalloproteinases [34]. In addition, IL-6 exhibits an effect on the subchondral bone, via activation of osteoclasts [35]. Also, in the mouse model, an effect was observed on the formation of osteophytes [36]. The IL-6 synovial and serum concentrations correlate in people with osteoarthritis with the radiographically detectable extent of joint changes [37].
When comparing the cytokine secretions and effects in the fracture area and the osteoarthritic joint, it is possible to conclude that at the start of fracture healing, the inflammatory process, controlled by the proinflammatory cytokines, allows the building and formation of cells, such as osteoblasts and osteoclasts, to migrate to the fracture area. In the osteoarthritic joint, the initial focus is on the destruction of cartilage, which, following through on the hypothesis, can be seen as a preparatory measure to induce the migration of osteoblasts and osteoclasts from the surrounding tissue, especially the subchondral bone.
Apart from a comparable presence of cytokines in the fracture area and the osteoarthritic joint, one also encounters a similar situation in the mesenchymal stem cells, which underlines their significant role in both mechanisms. Mesenchymal stem cells demonstrate the ability to differentiate into different cell types, such as osteoblasts and chondroblasts [38][39][40]. In the fracture area, they represent the essential cells needed for healing. In the osteoarthritic joint, their proliferation behavior is reduced, except for osteogenic differentiation [41]. This suggests that the formation of bone material in the osteoarthritic joint, unlike cartilage, is not affected.
The second phase: The second phase of bone healing, the so-called soft callus, follows the inflammation phase. The mesenchymal stem cells that have migrated from the surrounding soft tissue, the cortical bone, bone marrow or via the blood differentiate into chondrocytes, which form the soft callus by means of forming the extracellular matrix [42]. The extracellular matrix is composed of collagens (I and II) and proteoglycans. TGF-ßs and BMPs are described as important factors in the formation of soft callus. Among the TGF-ß and BMP subfactors, TGF-ß1 and BMP-2, -4, -5, -6 seem to play a more significant role in the formation of soft callus [6,43-46]. Furthermore, angiogenic factors, such as VEGF, are involved in the callus formation by promoting the growth of new blood vessels in the fracture area [47][48].
The same structural changes as with soft callus are also found during osteoarthritic joint remodeling, which includes connective tissue capsule thickening and osteophytic changes. A study on the gene expression of osteophytic cells found an expression pattern similar to the cells of soft callus [49]. The significance of cytokines and/or growth factors TGF, BMP and VEGF in the osteoarthritic joint has also been described. An increased concentration of TGF-ß1 was detected in the synovia of osteoarthritic temporomandibular joints.
Increased concentration of BMPs was measured several times in osteoarthritic joints, and relations to the degree of destruction in the joint have been observed [54][55][56]. The significance of VEGF in the genesis of osteoarthritis is underscored by the observation that the inhibition of VEGF reduces the progression of osteoarthritis [57]. Thus, there are also structural and functional similarities between the second phase of fracture healing and osteoarthritis. While in fracture healing incipient stability is to be achieved through the soft callus, the osteoarthritic counterpart marks the beginning of joint stiffness and, thus, the preparatory phase of ancylosis.
The Third phase: The third phase of bone healing, the formation of hard callus, is also referred to as primary bone formation [58]. Supported by the high activity of osteoblasts, mineralizing bone matrix forms. This can involve both types of ossification, intramembranous and endochondral ossification. The BMPs play a key role in controlling these processes [59][60]. The significance of angiogenic factors at this time of bone formation has also been discussed [61][62].
The active cells and growth factors in the formation of the hard callus can also be detected in the osteoarthritic joint, and in particular are tied to the formation of osteophytes [63]. It has also been debated whether BMPs have any significance in the capsule thickening [64]. This suggests that the osteophytic changes have a stabilizing effect on the joint to support the subsequent ossification. This theory is supported by the observation that osteophytes particularly occur at locations of the greatest movement.
Final phase: The final phase of bone healing is the formation of a physiological, spongiform bone tissue from the, as yet undifferentiated, hard callus, and is also called secondary bone formation [58]. Apart from osteoblasts, osteoclasts are particularly active in this phase. The formation of the latter is controlled by cytokines. The macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor κβ ligand (RANKL) are known as pro-osteoclastic factors. The former induces the differentiation of osteoblasts from hematopoietic stem cells, while the latter coordinates the bone resorption [65][66]. Osteoprotegerin, another factor, regulates the signal induction of RANKL [67-68].
In addition to the forming cells, all factors described have been detected also in the osteoarthritic joint [69-70]. This, then, leads to the final joint remodeling followed by final ancylosis, and thus also to the reconstruction into stable bone tissue.

Conclusion
From the above, it follows that there is a clear congruence between osteoarthritic joint remodeling and bone healing. Apart from the factors described, there are certainly further factors that are active in both mechanisms, but it is unlikely, should they be discovered, that they will substantially alter the hypothesis presented herein. The hypothesis presented herein can serve as a basis for new treatment options for osteoarthritic joints.