Trends in Pharmacological Sciences
ReviewTargeting TGFβ signaling in subchondral bone and articular cartilage homeostasis
Section snippets
Current understanding of OA and treatment
OA is a noninflammatory degenerative joint disease and the leading cause of physical disability [1]. Approximately 27 million people suffer from OA in the USA alone [2]. OA represents an enormous societal burden that increases greatly as the population ages. Clinically, OA is described by joint pain and functional impairment including tenderness and limitation of movement [3]; pathologically, OA is characterized by degeneration of cartilage accompanied by sclerosis of subchondral bone and
Temporospatial activation of ECM latent TGFβ
There are more than 40 members in the TGFβ superfamily, which is further classified into four major subfamilies 22, 23. The TGFβ subfamily contains three closely related mammalian isoforms, TGFβ1, -β2 and -β3, that all function through the same receptor signaling systems 24, 25. TGFβs are different from other cytokines and factors in that, upon secretion, they are deposited into the ECM of different tissues in an inactive, latent form. TGFβ is synthesized as a large precursor molecule which
Activation of latent TGFβ in the matrix maintains bone homeostasis during remodeling
Adult bone is a dynamic tissue in constant remodeling that is continuously being formed and resorbed. The remodeling process is necessary to maintain the structural integrity of the skeleton and allows the repair of tissue damage and homeostasis of calcium and phosphorous metabolism [53]. This bone remodeling is accomplished by precise coordination of osteoblasts and osteoclasts [54]. Bone resorption and formation do not occur randomly along the bone surface. Rather, they occur at specific
Dynamic changes in bone microenvironment during bone remodeling
It is known that bone marrow has an organized and structured architecture, and the behavior of MSCs is precisely regulated in this highly dynamic microenvironment. MSCs serve to replenish the differentiated compartment of various cell types for bone formation, angiogenesis, adipogenesis, and chondrogenesis 43, 61, 62, 63, 64, 65. Extrinsic signals in the surrounding microenvironment that are transmitted to the stem cell niche substantially influence MSC self-renewal or differentiation. TGFβ
Activation of matrix TGFβ in articular cartilage homeostasis
The indispensable role of TGFβ in maintenance of articular cartilage metabolic homeostasis and structural integrity has been well established [73]. TGFβ stimulates early events in chondrogenesis, including chondrogenic condensation and chondroprogenitor cell proliferation and differentiation 74, 75, 76, 77. It also inhibits terminal differentiation of chondrocytes, thereby blocking cartilage matrix calcification and vascularization to maintain ECM integrity [78]. Interruption of TGFβ signaling
High level of active TGFβ in the subchondral bone at onset of OA
The structure of bone dynamically changes in response to mechanical loading, particularly when joint stability is decreased in patients during aging or with ligament injury or obesity. Recent studies show that osteocytes regulate the dynamic nature of bone through diverse functions [123]. Osteocytes are now recognized as the principal sensors for mechanical loading and are able to transduce mechanical signals into biological responses [124]. The activities of both osteoblasts and osteoclasts
Modulation of TGFβ activity in subchondral bone as a potential therapy for OA
Several studies of human OA have pointed to subchondral bone as a site for pharmaceutical intervention. Increased osteoclast activity and bone turnover rate are known pathological characteristics of subchondral bone in OA, particularly in the early stages. For this reason the common anti-resorptive medicine, bisphosphonate, has been tested its efficacy for treating OA in many clinical trials [134]. Although the outcome in human subjects was not as encouraging as in animal OA models 135, 136, 137
Concluding remarks
Articular cartilage and subchondral bone constantly interact as a functional unit during joint movements. TGFβ plays a crucial role in maintenance of both bone and articular cartilage homeostasis. Aberrant activation TGFβ1 in the subchondral bone leads to abnormal bone remodeling and the formation of marrow osteroid islets. Importantly, the abnormal subchondral bone structure alters the stress distribution on the articular cartilage and results in degeneration of articular cartilage. The
Acknowledgements
This work was supported in part by the NIH grants AR 06394 and DK 057501 (both to Xu Cao).
Glossary
- ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs)
- a family of peptidases that process procollagens and von Willebrand factor as well as cleaving aggrecan, versican, brevican, and neurocan.
- Arthroscopy
- a minimally invasive surgical procedure in which an examination and sometimes treatment of damage of the interior of a joint is performed using an arthroscope, a type of endoscope that is inserted into the joint through a small incision.
- Articular cartilage
- cartilage that covers
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