Related Experiment Video

Updated: May 28, 2026

A Novel in vivo Gene Transfer Technique and in vitro Cell Based Assays for the Study of Bone Loss in Musculoskeletal Disorders
11:47

A Novel in vivo Gene Transfer Technique and in vitro Cell Based Assays for the Study of Bone Loss in Musculoskeletal Disorders

Published on: June 8, 2014

Kindlin-2 functional restoration through methylmalonic acid clearance by coenzyme A counteracts osteoporosis

Xuling Li1, Guixing Ma1, Fen Wang1

  • 1Department of Biochemistry, SUSTech Homeostatic Medicine Institute, School of Medicine, Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Shenzhen Key Laboratory of Cell Microenvironment, Key University Laboratory of Metabolism and Health of Guangdong, Southern University of Science and Technology, Shenzhen 518055, China.

Molecular Therapy : the Journal of the American Society of Gene Therapy
|May 27, 2026
PubMed

Insights

Old blood components accelerate skeletal aging by increasing methylmalonic acid (MMA). This molecule targets Kindlin-2, but coenzyme A (CoA) can reverse these effects, offering a potential therapy for osteoporosis.

Area of Science:

  • Biogerontology
  • Skeletal Biology
  • Molecular Mechanisms of Aging

Background:

  • Old blood is known to induce senescence, but the specific molecular drivers of age-related skeletal decline are not fully understood.
  • Non-protein components of aged serum contribute to skeletal aging phenotypes in younger organisms.

Purpose of the Study:

  • To identify the key molecular components in aged serum responsible for inducing skeletal aging.
  • To elucidate the mechanism by which these components affect bone health.
  • To explore potential therapeutic interventions for age-related bone loss.

Main Methods:

  • Administration of aged human serum (non-protein components) to young mice.
  • Identification of methylmalonic acid (MMA) as a key aging factor using biochemical assays.
  • Photoaffinity labeling to identify the intracellular receptor for MMA.
  • Analysis of MMA binding to Kindlin-2 and its downstream effects (ubiquitination, degradation).
  • Treatment with coenzyme A (CoA) to assess its therapeutic potential in mouse models of aging and estrogen deficiency.

Main Results:

  • Non-protein components of aged human serum (ONP) induced skeletal aging in young mice.
  • Methylmalonic acid (MMA) was identified as a key driver of these aging phenotypes.
  • Kindlin-2 was confirmed as a direct intracellular MMA receptor, with MMA binding promoting its degradation.
  • Coenzyme A (CoA), an endogenous MMA scavenger, reversed MMA- and ONP-induced skeletal aging.
  • CoA treatment also protected against age-related bone loss and bone mass reduction in aged and estrogen-deficient mice.

Conclusions:

  • Methylmalonic acid (MMA) is a critical factor in age-related skeletal decline, acting via the intracellular receptor Kindlin-2.
  • Targeting MMA or enhancing its clearance, for example, with coenzyme A (CoA), represents a promising therapeutic strategy for osteoporosis and other age-related bone diseases.
Keywords:
Kindlin-2coenzyme Amethylmalonic acidosteoporosisserum non-protein componentsskeletal aging

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