Targeting TGFβ signaling in subchondral bone and articular cartilage homeostasis

doi:10.1016/j.tips.2014.03.005

Trends in Pharmacological Sciences

Volume 35, Issue 5, May 2014, Pages 227-236

https://doi.org/10.1016/j.tips.2014.03.005 Get rights and content

Highlights

•
Articular cartilage and subchondral bone act as a functional unit.
•
TGFβ maintains homeostasis of articular cartilage and subchondral bone.
•
Spatial and temporal activation of TGFβ is a prerequisite for its function.
•
Aberrant activation of TGFβ contributes to the onset of osteoarthritis (OA).
•
Improvement of the microenvironment in subchondral bone has potential in OA treatment.

Osteoarthritis (OA) is the most common degenerative joint disease and no disease-modifying therapy for OA is currently available. Targeting articular cartilage alone may not be sufficient to halt this disease progression. Articular cartilage and subchondral bone act as a functional unit. Increasing evidence indicates that transforming growth factor β (TGFβ) plays a crucial role in maintaining homeostasis of both articular cartilage and subchondral bone. Activation of extracellular matrix (ECM) latent TGFβ at the appropriate time and location is a prerequisite for its function. Aberrant activation of TGFβ in the subchondral bone in response to an abnormal mechanical loading environment induces formation of osteroid islets at the onset of OA. As a result, alteration of subchondral bone structure changes the stress distribution on the articular cartilage and leads to its degeneration. Thus, inhibition of TGFβ activity in the subchondral bone may provide a new avenue of treatment for OA. In this review we will discuss the role of TGFβ in the homeostasis of articular cartilage and subchondral bone as a novel target for OA therapy.

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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Trends in Pharmacological Sciences

ReviewTargeting TGFβ signaling in subchondral bone and articular cartilage homeostasis

Highlights

Section snippets

Current understanding of OA and treatment

Temporospatial activation of ECM latent TGFβ

Activation of latent TGFβ in the matrix maintains bone homeostasis during remodeling

Dynamic changes in bone microenvironment during bone remodeling

Activation of matrix TGFβ in articular cartilage homeostasis

High level of active TGFβ in the subchondral bone at onset of OA

Modulation of TGFβ activity in subchondral bone as a potential therapy for OA

Concluding remarks

Acknowledgements

Glossary

Gene

Osteoarthritis Cartilage

Osteoarthritis Cartilage

J. Biol. Chem.

Prog. Growth Factor Res.

Adv. Cancer Res.

Curr. Opin. Cell Biol.

Int. J. Biochem. Cell Biol.

Eur. J. Cell Biol.

Cytokine Growth Factor Rev.

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

Cell

Vitam. Horm.

Cell

Cell

Am. J. Pathol.

Curr. Opin. Cell Biol.

Osteoarthritis Cartilage

Arch. Biochem. Biophys.

Biophys. J.

Dev. Biol.

Osteoarthritis Cartilage

Biochim. Biophys. Acta

Osteoarthritis Cartilage

Am. J. Pathol.

Am. J. Pathol.

Projections of US prevalence of arthritis and associated activity limitations

Arthritis Rheum.

Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part II

Arthritis Rheum.

Osteoarthritis: symptoms, signs and source of pain

Inflammopharmacology

Cartilage biology in osteoarthritis – lessons from developmental biology

Nat. Rev. Rheumatol.

Mechanisms of disease: role of chondrocytes in the pathogenesis of osteoarthritis – structure, chaos and senescence

Nat. Clin. Pract. Rheumatol.

An aspartic acid repeat polymorphism in asporin inhibits chondrogenesis and increases susceptibility to osteoarthritis

Nat. Genet.

Identification of a central role for complement in osteoarthritis

Nat. Med.

Hypoxia-inducible factor-2alpha is a catabolic regulator of osteoarthritic cartilage destruction

Nat. Med.

Syndecan-4 regulates ADAMTS-5 activation and cartilage breakdown in osteoarthritis

Nat. Med.

Deletion of active ADAMTS5 prevents cartilage degradation in a murine model of osteoarthritis

Nature

Postnatal expression in hyaline cartilage of constitutively active human collagenase-3 (MMP-13) induces osteoarthritis in mice

J. Clin. Invest.

Recent progress in understanding molecular mechanisms of cartilage degeneration during osteoarthritis

Ann. N. Y. Acad. Sci.

Pharmacologic therapy for osteoarthritis – the era of disease modification

Nat. Rev. Rheumatol.

The bone–cartilage unit in osteoarthritis

Nat. Rev. Rheumatol.

Examination of subchondral bone architecture in experimental osteoarthritis by microscopic computed axial tomography

Arthritis Rheum.

The subchondral bone: a new frontier in articular cartilage repair

Knee Surg. Sports Traumatol. Arthrosc.

Alterations in periarticular bone and cross talk between subchondral bone and articular cartilage in osteoarthritis

Ther. Adv. Musculoskelet. Dis.

The importance of subchondral bone in osteoarthrosis

Curr. Opin. Rheumatol.

Expression and action of transforming growth factor beta (TGFbeta1, TGFbeta2, and TGFbeta3) during embryonic rat testis development

Biol. Reprod.

Review
Targeting TGFβ signaling in subchondral bone and articular cartilage homeostasis